病毒聚合酶及其調(diào)節(jié)的制作方法

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專利名稱：病毒聚合酶及其調(diào)節(jié)的制作方法
背景技術(shù)：
發(fā)明領(lǐng)域本發(fā)明提供了乙型肝炎病毒(HBV)聚合酶逆轉(zhuǎn)錄酶(rt)結(jié)構(gòu)域的三級(jí)結(jié)構(gòu)，從其對(duì)變體HBV聚合酶的突變進(jìn)行了繪圖，該HBV聚合酶的突變與抗病毒藥物的抗性或?qū)共《舅幬锞哂薪档偷拿舾卸认嚓P(guān)。本發(fā)明進(jìn)一步提供了鑒定、設(shè)計(jì)和/或改進(jìn)藥劑的方法，該藥劑基于三級(jí)結(jié)構(gòu)提供的原子坐標(biāo)能夠調(diào)節(jié)HBV聚合酶的功能活性。本發(fā)明再進(jìn)一步提供了調(diào)節(jié)HBV聚合酶功能活性的方法以及用于此的藥劑。根據(jù)本發(fā)明方法鑒定的藥劑特別用于治療和/或預(yù)防對(duì)抗病毒藥物呈現(xiàn)抗性或降低敏感度的HBV的感染。該藥劑還具有作為診斷劑的用途，如分辨抗性突變。此外，本發(fā)明能夠反應(yīng)待預(yù)測(cè)的特別的潛在抗病毒藥物。此外，鑒定了聚合酶內(nèi)的新靶點(diǎn)。
現(xiàn)有技術(shù)的描述本說(shuō)明書(shū)中涉及的出版物的文獻(xiàn)詳述集中于說(shuō)明書(shū)的結(jié)尾。
本說(shuō)明書(shū)中對(duì)任何現(xiàn)有技術(shù)的引用不是也不應(yīng)當(dāng)被認(rèn)為是認(rèn)可或任何形式的建議該現(xiàn)有技術(shù)在任何國(guó)家構(gòu)成了常規(guī)知識(shí)的一部分。
HBV是全世界慢性肝炎的主要起因。盡管可以獲得安全而有效的疫苗，HBV的世界流行還沒(méi)有顯著減少，因此導(dǎo)致選擇性抗病毒藥劑的需要。HBV是小的、部分雙鏈DNA病毒，其通過(guò)RNA中間物質(zhì)來(lái)復(fù)制。發(fā)展抗HBV藥劑的大多數(shù)努力瞄準(zhǔn)了具有逆轉(zhuǎn)錄酶活性的病毒DNA聚合酶。目前，大多數(shù)有遠(yuǎn)景的抗HBV藥劑是干擾病毒DNA復(fù)制的核苷類似物。盡管之前的核苷類似物如fialuridine(FLAU)已經(jīng)顯示了不可接受的毒性，較新的類似物如拉米夫定(3TC/LMV)、BMS-200、475和Adefovir Dipivoxial(ADV)已經(jīng)證明了臨床用途。尤其是，LMV的使用對(duì)發(fā)展用于對(duì)抗HBV的其它L-光學(xué)異構(gòu)核苷類似物產(chǎn)生了相當(dāng)大的興趣。
迄今，已經(jīng)使用體外試驗(yàn)來(lái)篩選小分子對(duì)抗HBV聚合酶的活性。盡管這樣的篩選技術(shù)有助于呈現(xiàn)抗病毒活性分子的初級(jí)鑒定，這樣的技術(shù)沒(méi)有提供合理設(shè)計(jì)或改進(jìn)結(jié)合病毒聚合酶的藥劑的范圍，以便來(lái)最大化其功能影響。合理設(shè)計(jì)需要聚合酶三級(jí)結(jié)構(gòu)的詳細(xì)知識(shí)，尤其是核苷酸結(jié)合口袋。
迄今，多數(shù)聚合酶分子已經(jīng)明確為大腸桿菌(Escherichia coli)DNA聚合酶I、HIV-1逆轉(zhuǎn)錄酶和噬菌體T7 RNA聚合酶的克列諾片段(Sawaya等，Science 2641930-1935，1994)?；诤腿嗣庖呷毕莶《?HIV)逆轉(zhuǎn)錄酶的同源性，已經(jīng)發(fā)展了幾組HBV聚合酶的結(jié)構(gòu)模型(Bartholomeusz等，Viral Hepatitis reviews 4167-187，1998；Allen等，Hepatology 27(6)1670-1677，1998；Das等，V.Virol.75(10)4771-4779，2001；Sawaya，1944，出處同前)。HIV聚合酶和所得到的HBV模型描述為具有“右手結(jié)構(gòu)”。所有聚合酶的手掌子域(

圖1，1)具有顯著的氨基酸同源性。C結(jié)構(gòu)域中YMDD基序的兩個(gè)保守天冬氨酸殘基(圖2，2)形成部分β折疊(Rodgers等，Proc.Natl.Acad.Sci.USA 92(4)1222-1226，1995)。A結(jié)構(gòu)域中的保守天冬氨酸殘基(圖1，3)在β折疊中兩個(gè)保守天冬氨酸殘基的鄰近，并與它們一起形成部分活性位點(diǎn)。HIV中，該活性位點(diǎn)是空腔的一部分，該空腔在一側(cè)與結(jié)構(gòu)域B的保守氨基酸殘基構(gòu)成的α螺旋相連。α螺旋的這些氨基酸殘基位于結(jié)合的模板-引物的模板鏈附近并形成部分結(jié)構(gòu)域B的模板夾(103、104、105)。Wrobel等(Proc.Natl.Acad.Sci.USA 95(2)638-645，1998)檢測(cè)了與X-射線晶體結(jié)構(gòu)相比較許多HIV鏈的遺傳變異性。他們發(fā)現(xiàn)不同的HIV株之間預(yù)測(cè)為外部的結(jié)構(gòu)高度可變，而功能/催化殘基(尤其在預(yù)測(cè)的核苷酸結(jié)合口袋中的)高度保守。
在促進(jìn)設(shè)計(jì)或改進(jìn)HBV聚合酶調(diào)節(jié)劑中，蛋白質(zhì)氨基酸序列的初級(jí)甚至二級(jí)結(jié)構(gòu)的知識(shí)是不夠的。相反，需要了解主體病毒聚合酶精確的三級(jí)結(jié)構(gòu)，以便來(lái)測(cè)定對(duì)功能(如模板結(jié)合和dNTP結(jié)合)關(guān)鍵性的殘基。因此，為了調(diào)節(jié)這樣聚合酶的活性并借此提供用于治療和/或預(yù)防如對(duì)抗病毒藥劑(如ADV)已經(jīng)變得沒(méi)有反應(yīng)的HBV藥劑感染之病癥的藥劑的目的，需要從對(duì)特定核苷類似物抗性的HBV闡明HBV聚合酶的結(jié)構(gòu)，以便有助于小分子篩選和合理的藥物設(shè)計(jì)/改進(jìn)。
最近，批準(zhǔn)了LMV治療慢性HBV感染(Dienstag，等，N.Engl.J.Med.3411256-1263，1999)。LMV是有效對(duì)抗人免疫缺陷病毒(HIV)和HBV的雙脫氧胞苷類似物(Coates，等，Antimicrob.Agents Chemother.36733-739，1992；Doong，等，Proc.Natl.Acad.Sci.USA888495-8499，1991)。還顯示了LMV作為對(duì)抗病毒DNA合成的鏈終止子(Zhu等，Antimicrob.Agents Chemother.421905-1810，1998)。然而，長(zhǎng)期的LMV治療導(dǎo)致治療一年中，17至46％患者出現(xiàn)了LMV-抗性HBV突變，治療兩年內(nèi)高于50％的患者出現(xiàn)(MV-抗性HBV突變)(Allen等，Hepatology 271670-1677，1998；Dienstag，等，1998，出處同前；Jarvis和Fauld，Drugs 58101-141，1999；Liaw，等，Hepatology 30567-572，1999)。藥物抗性HBV的出現(xiàn)強(qiáng)調(diào)了需要發(fā)展其它的抗病毒藥劑和治療策略。
HBV中，已經(jīng)很好地證明了LMV抗性，并主要與HBV聚合酶rtM204I/V(C結(jié)構(gòu)域)聯(lián)合rtL 180M(B結(jié)構(gòu)域)的改變相關(guān)。在LMV治療中以及法昔洛韋(FCV)治療中已經(jīng)選擇了HBV聚合酶中許多其他的氨基酸改變。
最近在HBV感染的患者中已經(jīng)描述了ADV抗性，并已經(jīng)在體外得到了證明。ADV抗性與rtN236T(結(jié)構(gòu)域D)+/-rtA181V/T(結(jié)構(gòu)域B)的突變相關(guān)。描述了聚合酶中這些突變的模型。
還鑒定了兩名患者的Entecavir(ETV)抗性。第一名患者中，除了rtM204V和rtL180M LMV抗性突變以外，這與rtA38E、rtT184G(結(jié)構(gòu)域B)和rtS202I(C結(jié)構(gòu)域)的突變相關(guān)。當(dāng)rtT184G和rtS202I兩者的改變結(jié)合LMV-R突變時(shí)，表型抗病毒測(cè)試表明了降低的ETV敏感度。第二名患者中，檢測(cè)到rtI169T(B結(jié)構(gòu)域)和rtM250V(E結(jié)構(gòu)域)的ETV抗性突變以及rtL180M、rtM204V和rtV173V/L的LMV抗性突變。
此外，已經(jīng)闡明了野生型HBV聚合酶rt結(jié)構(gòu)域的三級(jí)結(jié)構(gòu)。該唯一的三級(jí)結(jié)構(gòu)的闡明能夠合理分析、設(shè)計(jì)和/或改進(jìn)用于調(diào)節(jié)該抗病毒藥劑抗性HBV聚合酶功能活性的藥劑。該合理設(shè)計(jì)是基于野生型HBV聚合酶結(jié)構(gòu)特定突變的圖譜。這能夠從HBV如對(duì)抗病毒藥物如核苷類似物抗性的或呈現(xiàn)降低敏感度的HBV來(lái)鑒定藥劑，該藥劑能夠與任何HBV聚合酶相互作用。本發(fā)明進(jìn)一步能夠?qū)共《舅幬锝Y(jié)合口袋的其它部分進(jìn)行作圖。此外，模型可以用于鑒定對(duì)抗病毒藥劑是有用靶點(diǎn)的其它區(qū)域。
發(fā)明概述貫穿本說(shuō)明書(shū)，除非文中另外需要，詞語(yǔ)“包括”或變形如“包含”或“包含含有”，將理解為意味著包括所述的要素或整體或一組要素或整體，但不排除任何其它的要素或整體或一組要素或整體。
通過(guò)序列識(shí)別符編號(hào)(SEQ ID NO)來(lái)提及核苷酸和氨基酸序列。SEQ ID NO在數(shù)值上對(duì)應(yīng)序列識(shí)別符<400>1(SEQ ID NO1)、<400>2(SEQ ID NO2)，等。序列識(shí)別符的匯總提供于表1中。序列表提供于權(quán)利要求后。
氨基酸序列中特定的突變?cè)诖吮硎緸椤癤aa1nXaa2”，其中Xaa1是突變前的原始氨基酸殘基，n是殘基數(shù)，Xaa2是突變氨基酸?？s寫(xiě)“Xaa”可以是三個(gè)字母或單個(gè)字母(即“X”)的密碼子。“Xaa1nXaa2”前的“rt”意思是“逆轉(zhuǎn)錄酶”?！皊”意思是包膜基因。HBV DNA聚合酶的氨基酸殘基是用基序Tyr Met Asp Asp(YMDD)中的殘基甲硫氨酸編號(hào)為殘基編號(hào)204(Stuyver等，Hepatology 33751-757，2001)。乙型肝炎病毒表面抗原的氨基酸殘基是根據(jù)Norder等(J.Gen.Virol.74341-1348，1993)來(lái)編號(hào)的。單個(gè)或三個(gè)字母的縮寫(xiě)都可用來(lái)限定氨基酸殘基，這些總結(jié)于表2中。
本發(fā)明部分預(yù)測(cè)了野生型HBV聚合酶rt結(jié)構(gòu)域三級(jí)結(jié)構(gòu)的闡述。rt結(jié)構(gòu)域的三級(jí)結(jié)構(gòu)通過(guò)列于表6中的原子坐標(biāo)數(shù)據(jù)集限定。該闡明的結(jié)構(gòu)提供了分子基礎(chǔ)，用于對(duì)核苷類似物或其它抗病毒藥劑的抗性作出圖譜，因此可以鑒定、篩選、分析、合理設(shè)計(jì)和/或改進(jìn)藥劑，這些藥劑與特定的HBV聚合酶作用并任選地調(diào)節(jié)HBV聚合酶的功能活性。這些藥劑在治療和預(yù)防對(duì)抗病毒藥劑抗性的或呈現(xiàn)降低敏感度的HBV感染中可以特別地用作激動(dòng)劑或拮抗劑。它們還可以用作診斷劑如具有分辯對(duì)抗病毒藥物具有不同或相似抗性的HBV聚合酶變體的能力。
因此，本發(fā)明的一方面涉及來(lái)自HBV聚合酶逆轉(zhuǎn)錄酶(rt)結(jié)構(gòu)域的原子坐標(biāo)的數(shù)據(jù)集，其中所述原子坐標(biāo)列于表6中。
本發(fā)明的另一方面涉及鑒定藥劑的方法，該藥劑能夠與HBV聚合酶或其同系物、衍生物、類似物或片段相互作用并調(diào)節(jié)至少一種與所述聚合酶相關(guān)的功能活性，所述方法包括將所述聚合酶與藥劑接觸并測(cè)定所述藥劑與所述聚合酶相互作用的互補(bǔ)性的程度。
在一個(gè)優(yōu)選實(shí)施方案中，HBV聚合酶中的突變作圖于野生型rt結(jié)構(gòu)域突變HBV聚合酶，并通常具有至少一個(gè)以下的特征(i)與天然HBV聚合酶相比，顯示出對(duì)核苷類似物提高的抗性，核苷類似物例如但不限于ADV、LMV、FCV、FTC、ETV、DAPD、TDF和DXG；(ii)包含選自氨基酸殘基28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257或4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266片段中的突變，例如但不限于rtA21S，rtA38E，rtY54H，rtN76D，rtL91I，rtF122L，rtY124H，rtT128N，rtQ130P，rtT184G，rtM204V/I，rtS202I，rtH248N，rtY252L，rtS21A，rtN/S/T/I/V53D，rtY54H，rtS57P，rtL91I，rtS116P，rtL122F，rtF122L，rtN124H，rtY124H，rtH126R，rtY126Q，rtT128N，rtP130Q，rtD131N，rtV134D，rtY135C，rtY141Y/F，rtL145M，rtF151T/F，rtL180M，rtA181T，rtS202G，rtI204V，rtK212R，rtL217R，rtS219A，rtI235I/M，rtN236T，rtN238D，sP120T，sM125T，sS126T，sT127A，sT118R，sM133L/M，sM133T，sF134V，sS143S/T，sD144A，sG145A，sW172Stop，sI195M，sS207R，sY225Y/C，間隔基L97I，間隔基K115R，間隔基H116L，間隔基L128F，間隔基S137G，間隔基R139G，間隔基F142S，rtA97V，rtH126R，rtS135Y，rtM204I，PreS1 N114D，PreS1 T115S，PreS2 F22L，PreS2V39A，PreS2 P52L，sL89V，sT118A，sF161L，sE164D，sI195M，sI208T，PreS1E86Q，PreS1 N91K，PreS2 P41H，sQ30K，sP120T，sL176V，sV194F，rtS21A，rtL122F，rtN124H，rtH126R，rtP130Q，rtD131N，rtY135C，rtN/S/T/I/V53D，rtY126Q，rtS202G，rtI204V，rtI235I/M，sM125T，sT127A，sT118R，sM133T，sF134V，sI195M，sS207R，sY225Y/C，rtG172E，rtG174C，rtP177L，rtL180V，rtT184S，sR160N，sE164D，sF170L，sL175L/S，sQ181E/G/Q，sC/W182Y/STOP，sW196L，sW196S，sW196STOP，sM198I，sW199S，sS204T，sY206N，sS210K，sS210R，sL216STOP，sY255F，rtL77L/F，rtL77L/M/V，rtL80I，rtL80V，rtH90N/H，rtS117S/Y，rt125DELrt128，rtQ125K，rtQ125N，rtY126Q，rtL128L/M，rtT128A，rtL132L/M，rtN134G，rtS137T，rtN139H，rtN139K，rtY141Y/STOP，rtV/G142L，rtL147L/W，rtK149R，rtG153E，rtR153Q，rtW153S，rtW153Q，rtF166L，rtI169L，rtF178F/L，rtI187L，rtI187I/V，rtV191I，rtV191V/I，rtN202S，rtS202S/C，rtS202G，rtS213T，rtV/G214E，rtS219A，rtS219P，rtN/Q238H，rtN/S/H238N/K，rtN/S/H/T238/T/A/S/L，rtR242R/K，rtR242R/S，rtN248H，rtI253A，s118-207，s117-120DEL，sI68I/M，sC69F/L，sL109I/L，sG112R，sS17T，sT118R，sK122R，sT123P，sT126S，sT131N，sN131T，sM133K/M，sM133I，sY/F134S，sC139C/G，sK141E，sD144E，sG145R，rtT128T/I，rtL82M，rtT135C，rtT150A，rtV163I，rtT184S，rtA200V，rtF202V，rtS213T，rtQ215H，rtS219A，rtA222T，rtI224S，rtL229M，rtL235I，rtN238S，rtS78T，rt116DEL122，rtI163V，rtL180V，rtE8A，rtV23I，rtD31D/G，rtY53D，rtV58V/I，rtA/S21T，rtV/I/N/S/T53D，rt/I/N/S/T53Y，rtS/T/N/H/A54Y/H，PreS2 L11L/A，PreS2 R17I，DEL PreS2 18-21，PreS2 T30A，PreS2 N54H，sT13T/A，PreS2 Q1V，PreS2 Q1M，rtH90D，rtL/F108L，rtL157L/M，rtA181V，rtV207I，rtP109S，rtN/H/A/S/Q238K，s181M，sP214Q，sF83S，sL173F，sW199L，sI126T，sK160R，sS174N，sA84V，sS210N，sC69STOP/C，sC76Y，si110V/I，sY134N，sW172STOP/W，K32M/F/P/S/T/W/YV/A/R/N/D//C/Q/E/G/H/I/L/缺失；N33D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；P34S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；H35I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；T37W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；
P59S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；K60M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；F61P/S/T/W/Y/N/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；A62R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；V63A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；D83C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/缺失；V84A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；S85T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；A86R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/YV/缺失；Y89V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；H90I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；I/L91K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/缺失；P177S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；F178P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；L179K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；L180K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；A181R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Q183E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；F183P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；T184W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；Y203V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；M204F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；L235K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N236D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；T237W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P237S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；N238D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H238I/L/K/M/F/[/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；A238R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；S239T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；Q238E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；K239M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；
L247K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N248D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H248I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；F249P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；M250F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；G251H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/缺失；和V251A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；和/或(iii)包含SEQ ID NO1中所述的氨基酸序列或限定HBV聚合酶且在最佳比對(duì)后具有與SEQ ID NO1至少70％相似性序列的氨基酸序列。
本發(fā)明進(jìn)一步鑒定了涉及核苷或核苷酸類似物結(jié)合的HBV聚合酶中初級(jí)和二級(jí)氨基酸殘基。初級(jí)殘基位于位置編號(hào)28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257(圖16)。二級(jí)殘基位于位置編號(hào)4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266(圖16)。
因此，本發(fā)明擴(kuò)展至氨基酸殘基28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257，或4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266內(nèi)的任何突變，其賦予了對(duì)任何抗病毒藥物(如核苷或核苷酸類似物)的抗性或降低的敏感度。
一特別具體化的HBV聚合酶是對(duì)ADV抗性的并對(duì)野生型HBV聚合酶的三級(jí)結(jié)構(gòu)進(jìn)行了作圖。
本發(fā)明的另一方面提供了使用編程的計(jì)算機(jī)來(lái)鑒定藥劑的計(jì)算機(jī)輔助方法，該藥劑潛在地能夠結(jié)合HBV聚合酶的結(jié)構(gòu)域并任選地調(diào)節(jié)HBV聚合酶的至少一種功能活性，該方法包括步驟(a)將包括HBV聚合酶原子坐標(biāo)的數(shù)據(jù)輸入編程的計(jì)算機(jī)中，該聚合酶具有選自氨基酸殘基28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257，或4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266區(qū)域內(nèi)的突變，例如但不限于rtA21S，rtA38E，rtY54H，rtN76D，rtL91I，rtF122L，rtY124H，rtT128N，rtQ130P，rtT184G，rtM204V/I，rtS202I，rtH248N，rtY252L，rtS21A，rtN/S/T/I/V53D，rtY54H，rtS57P，rtL91I，rtS116P，rtL122F，rtF122L，rtN124H，rtY124H，rtH126R，rtY126Q，rtT128N，rtP130Q，rtD131N，rtV134D，rtY135C，rtY141Y/F，rtL145M，rtF151T/F，rtL180M，rtA181T，rtS202G，rtI204V，rtK212R，rtL217R，rtS219A，rtI235I/M，rtN236T，rtN238D，sP120T，sM125T，sS126T，sT127A，sT118R，sM133L/M，sM133T，sF134V，sS143S/T，sD144A，sG145A，sW172Stop，sI195M，sS207R，sY225Y/C，間隔基L97I，間隔基K115R，間隔基H116L，間隔基L128F，間隔基S137G，間隔基R139G，間隔基F142S，rtA97V，rtH126R，rtS 135Y，rtM204I，PreS 1N114D，PreS1T115S，PreS2F22L，PreS2V39A，PreS2P52L，sL89V，sT118A，sF161L，sE164D，sI195M，sI208T，PreS1E86Q，PreS 1N91K，PreS2P41H，sQ30K，sP120T，sL176V，sV194F，rtS21A，rtL122F，rtN124H，rtH126R，rtP130Q，rtD131N，rtY135C，rtN/S/T/I/V53D，rtY126Q，rtS202G，rtI204V，rtI235I/M，sM125T，sT127A，sT118R，sM133T，sF134V，sI195M，sS207R，sY225Y/C，rtG172E，rtG174C，rtP177L，rtL180V，rtT184S，sR160N，sE164D，sF170L，sL175L/S，sQ181E/G/Q，sC/W182Y/STOP，sW196L，sW196S，sW196STOP，sM198I，sW199S，sS204T，sY206N，sS210K，sS210R，sL216STOP，sY255F，rtL77L/F，rtL77L/M/V，rtL80I，rtL80V，rtH90N/H，rtS117S/Y，rt125DELrt128，rtQ125K，rtQ125N，rtY126Q，rtL128L/M，rtT128A，rtL132L/M，rtN134G，rtS137T，rtN139H，rtN139K，rtY141Y/STOP，rtV/G142L，rtL147L/W，rtK149R，rtG153E，rtR153Q，rtW153S，rtW153Q，rtF166L，rtI169L，rtF178F/L，rtI187L，rtI187I/V，rtV191I，rtV191V/I，rtN202S，rtS202S/C，rtS202G，rtS213T，rtV/G214E，rtS219A，rtS219P，rtN/Q238H，rtN/S/H238N/K，rtN/S/H/T238/T/A/S/L，rtR242R/K，rtR242R/S，rtN248H，rtI253A，s118-207，s117-120DEL，sI68I/M，sC69F/L，sL109I/L，sG112R，sS17T，sT118R，sK122R，sT123P，sT126S，sT131N，sN131T，sM133K/M，sM133I，sY/F134S，sC139C/G，sK141E，sD144E，sG145R，rtT128T/I，rtL82M，rtT135C，rtT150A，rtV163I，rtT184S，rtA200V，rtF202V，rtS213T，rtQ215H，rtS219A，rtA222T，rtI224S，rtLrt229M，rtL235I，rtN238S，rtS78T，rt116DEL122，rtI163V，rtL180V，rtE8A，rtV23I，rtD31D/G，rtY53D，rtV58V/I，rtA/S21T，rtV/I/N/S/T53D，rtV/I/N/S/T53Y，rtS/T/N/H/A54Y/H，PreS2L11L/A，PreS2 R17I，DEL PreS2 18-21，PreS2 T30A，PreS2 N54H，sT13T/A，PreS2 Q1V，PreS2 Q1M，rtH90D，rtL/F108L，rtL157L/M，rtA181V，rtV207I，rtP109S，rtN/H/A/S/Q238K，s181M，sP214Q，sF83S，sL173F，sW199L，sI126T，sK160R，sS174N，sA84V，sS210N，sC69STOP/C，sC76Y，si110V/I，sY134N，sW172STOP/W，K32M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；N33D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；P34S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；H35I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；T37W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P59S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；K60M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；F61P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；A62R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；V63A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；D83C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/缺失；V84A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；S85T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；A86R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/YV/缺失；Y89V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；H90I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；L/L91K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/缺失；P177S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；F178P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；L179K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；L180K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；A181R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Q183E/G/HI/L/K/M/F/P/S/T/W/Y/V/A/R/N//D/C/缺失；
F183P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；T184W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；Y203V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；M204F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；L235K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N236D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；T237W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P237S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；N238D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H238I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；A238R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；S239T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；Q238E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；K239M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；L247K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N248D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H248I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；F249P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；M250F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；G251H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/缺失；和V251A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；(b)使用計(jì)算機(jī)方法，產(chǎn)生與(a)中限定的原子坐標(biāo)具有立體化學(xué)互補(bǔ)性結(jié)構(gòu)的一套原子坐標(biāo)或其子集，由此產(chǎn)生標(biāo)準(zhǔn)數(shù)據(jù)集；(c)使用處理器，將標(biāo)準(zhǔn)數(shù)據(jù)集包括于化學(xué)結(jié)構(gòu)的計(jì)算機(jī)數(shù)據(jù)庫(kù)；(d)使用計(jì)算機(jī)方法，從數(shù)據(jù)庫(kù)中選擇與所述標(biāo)準(zhǔn)數(shù)據(jù)集的部分相似的化學(xué)結(jié)構(gòu)；和
(e)輸出所選擇的與標(biāo)準(zhǔn)數(shù)據(jù)集的部分相似的化學(xué)結(jié)構(gòu)。
優(yōu)選地，該方法進(jìn)一步包括獲得具有步驟(d)和(e)中所選化學(xué)結(jié)構(gòu)的藥劑，并測(cè)試化合物調(diào)節(jié)HBV聚合酶的至少一種功能活性的能力的步驟。
仍然是本發(fā)明的另一方面，提供了計(jì)算機(jī)或其軟件部分，用于產(chǎn)生分子或分子復(fù)合物的三級(jí)結(jié)構(gòu)圖像，其包括分子或分子復(fù)合物的同系物的三維圖像，其中同系物包括與氨基酸主鏈原子的標(biāo)準(zhǔn)差(rootmean square deviation)不大于1.5_的結(jié)構(gòu)域，其中計(jì)算機(jī)包括(a)機(jī)器可讀的數(shù)據(jù)存儲(chǔ)介質(zhì)，包括用機(jī)器可讀數(shù)據(jù)編碼的數(shù)據(jù)存儲(chǔ)材料，其中數(shù)據(jù)包括HBV聚合酶的結(jié)構(gòu)坐標(biāo)，該聚合酶具有選自氨基酸殘基28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257，或4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266區(qū)域內(nèi)的突變，例如但不限于rtA21S，rtA38E，rtY54H，rtN76D，rtL91I，rtF122L，rtY124H，rtT128N，rtQ130P，rtT184G，rtM204V/I，rtS202I，rtH248N，rtY252L，rtS21A，rtN/S/T/I/V53D，rtY54H，rtS57P，rtL91I，rtS116P，rtL122F，rtF122L，rtN124H，rtY124H，rtH126R，rtY126Q，rtT128N，rtP130Q，rtD131N，rtV134D，rtY135C，rtY141Y/F，rtL145M，rtF151T/F，rtL180M，rtA181T，rtS202G，rtI204V，rtK212R，rtL217R，rtS219A，rtI235I/M，rtN236T，rtN238D，sP120T，sM125T，sS126T，sT127A，sT118R，sM133L/M，sM133T，sF134V，sS143S/T，sD144A，sG145A，sW172Stop，sI195M，sS207R，sY225Y/C，間隔基L97I，間隔基K115R，間隔基H116L，間隔基L128F，間隔基s137G，間膈基R139G，間隔基F142s，rtA97V，rtH126R，rtS135Y，rtM204I，PreS1N114D，PreS 1T115S，PreS2F22L，PreS2V39A，PreS2P52L，sL89V，sT118A，sF161L，sE164D，sI195M，sI208T，PreS 1E86Q，PreS 1N91K，PreS2P41H，sQ30K，sP120T，sL176V，sV194F，rtS21A，rtL122F，rtN124H，rtH126R，rtP130Q，rtD131N，rtY135C，rtN/S/T/I/V53D，rtY126Q，rtS202G，rtI204V，rtI235I/M，sM125T，sT127A，sT118R，sM133T，sF134V，sI195M，sS207R，sY225Y/C，rtG172E，rtG174C，rtP177L，rtL180V，rtT184S，sR160N，sE164D，sF170L，sL175L/S，sQ181E/G/Q，sC/W182Y/STOP，sW196L，sW196S，sW196STOP，sM198I，sW199S，sS204T，sY206N，sS210K，sS210R，sL216STOP，sY255F，rtL77L/F，rtL77L/M/V，rtL80I，rtL80V，rtH90N/H，rtS117S/Y，rt125DELrt128，rtQ125K，rtQ125N，rtY126Q，rtL128L/M，rtT128A，rtL132L/M，rtN134G，rtS137T，rtN139H，rtN139K，rtY141Y/STOP，rtV/G142L，rtL147L/W，rtK149R，rtG153E，rtR153Q，rtW153S，rtW153Q，rtF166L，rtI169L，rtF178F/L，rtI187L，rtI187I/V，rtV191I，rtV191V/I，rtN202S，rtS202S/C，rtS202G，rtS213T，rtV/G214E，rtS219A，rtS219P，rtN/Q238H，rtN/S/H238N/K，rtN/S/H/T238/T/A/S/L，rtR242R/K，rtR242R/S，rtN248H，rtI253A，s118-207，s117-120DEL，sI68I/M，sC69F/L，sL109I/L，sG112R，sS17T，sT118R，sK122R，sT123P，sT126S，sT131N，sN131T，sM133K/M，sM133I，sY/F134S，sC139C/G，sK141E，sD144E，sG145R，rtT128T/I，rtL82M，rtT135C，rtT150A，rtV163I，rtT184S，rtA200V，rtF202V，rtS213T，rtQ215H，rtS219A，rtA222T，rtI224S，rtL229M，rtL235I，rtN238S，rtS78T，rt116DEL122，rtI163V，rtL180V，rtE8A，rtV23I，rtD31D/G，rtY53D，rtV58V/I，rtA/S21T，rtV/I/N/S/T53D，rtV/I/N/S/T53Y，rtS/T/N/H/A54Y/H，PreS2L11L/A，PreS2 R17I，DEL PreS2 18-21，PreS2 T30A，PreS2 N54H，sT13T/A，PreS2Q1V，PreS2Q1M，rtH90D，rtL/F108L，rtL157L/M，rtA181V，rtV207I，rtP109S，rtN/H/A/S/Q238K，s181M，sP214Q，sF83S，sL173F，sW199L，sI126T，sK160R，sS174N，sA84V，sS210N，sC69STOP/C，sC76Y，si110V/I，sY134N，sW172STOP/W，K32M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；N33D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；P34S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；H35I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；T37W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P59S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；K60M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；F61P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；A62R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；
V63A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；D83C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/缺失；V84A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；S85T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；A86R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/YV/缺失；Y89V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；H90I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；I/L91K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/缺失；P177S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；F178P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；L179K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；L180K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；A181R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Q183E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；F183P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；T184W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；Y203V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；M204F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；L235K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N236D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；T237W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P237S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；N238D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H238I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；A238R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；S239T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；Q238E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；K239M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；L247K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N248D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H248I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；F249P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；M250F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；
G251H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/缺失；和V251A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；(b)用于存儲(chǔ)處理機(jī)器可讀數(shù)據(jù)的指令的工作存儲(chǔ)器；(c)連接于工作存儲(chǔ)器和機(jī)器可讀數(shù)據(jù)存儲(chǔ)介質(zhì)的中央處理單元，用于將機(jī)器可讀數(shù)據(jù)處理成三維圖像；和(d)連接于中央處理單元的顯示器，用于顯示三維結(jié)構(gòu)圖像。
一實(shí)施方案中，三維結(jié)構(gòu)圖像是通過(guò)列于表6中的一套結(jié)構(gòu)坐標(biāo)限定的HBV聚合酶rt，或其中三維圖像是分子或分子復(fù)合物的同系物，該同系物具有與氨基酸主鏈原子的不大于1.5_的標(biāo)準(zhǔn)差。
本發(fā)明的另一方面提供了計(jì)算機(jī)或其軟件，其用于測(cè)定對(duì)應(yīng)于包含HBV聚合酶rt的分子或分子復(fù)合物三維結(jié)構(gòu)的至少部分結(jié)構(gòu)坐標(biāo)，其中計(jì)算機(jī)包括(a)機(jī)器可讀數(shù)據(jù)存儲(chǔ)介質(zhì)，包括用機(jī)器可讀數(shù)據(jù)編碼的數(shù)據(jù)存儲(chǔ)材料，其中數(shù)據(jù)包含至少部分HBV聚合酶的結(jié)構(gòu)坐標(biāo)，該聚合酶具有選自氨基酸殘基28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257，或4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266區(qū)域內(nèi)的突變，諸如但不限于rtA21S，rtA38E，rtY54H，rtN76D，rtL91I，rtF122L，rtY124H，rtT128N，rtQ130P，rtT184G，rtM204V/I，rtS202I，rtH248N，rtY252L，rtS21A，rtN/S/T/I/V53D，rtY54H，rtS57P，rtL91I，rtS116P，rtL122F，rtF122L，rtN124H，rtY124H，rtH126R，rtY126Q，rtT128N，rtP130Q，rtD131N，rtV134D，rtY135C，rtY141Y/F，rtL145M，rtF151T/F，rtL180M，rtA181T，rtS202G，rtI204V，rtK212R，rtL217R，rtS219A，rtI235I/M，rtN236T，rtN238D，sP120T，sM125T，sS126T，sT127A，sT118R，sM133L/M，sM133T，sF134V，sS143S/T，sD144A，sG145A，sW172Stop，sI195M，sS207R，sY225Y/C，間隔基L97I，間隔基K115R，間隔基H116L，間隔基L128F，間隔基S137G，間隔基R139G，間隔基F142S，rtA97V，rtH126R，rtS135Y，rtM204I，PreS1N114D，PreS1T115S，PreS2F22L，PreS2V39A，PreS2P52L，sL89V，sT118A，sF161L，sE164D，sI195M，sI208T，PreS1E86Q，PreS1N91K，PreS2P41H，sQ30K，sP120T，sL176V，sV194F，rtS21A，rtL122F，rtN124H，rtH126R，rtP130Q，rtD131N，rtY135C，rtN/S/T/I/V53D，rtY126Q，rtS202G，rtI204V，rtI235I/M，sM125T，sT127A，sT118R，sM133T，sF134V，sI195M，sS207R，sY225Y/C，rtG172E，rtG174C，rtP177L，rtL180V，rtT184S，sR160N，sE164D，sF170L，sL175L/S，sQ181E/G/Q，sC/W182Y/STOP，sW196L，sW196S，sW196STOP，sM198I，sW199S，sS204T，sY206N，sS210K，sS210R，sL216STOP，sY255F，rtL77L/F，rtL77L/M/V，rtL80I，rtL80V，rtH90N/H，rtS117S/Y，rt125DELrt128，rtQ125K，rtQ125N，rtY126Q，rtL128L/M，rtT128A，rtL132L/M，rtN134G，rtS137T，rtN139H，rtN139K，rtY141Y/STOP，rtV/G142L，rtL147L/W，rtK149R，rtG153E，rtR153Q，rtW153S，rtW153Q，rtF166L，rtI169L，rtF178F/L，rt187L，rtI187I/V，rtV191I，rtV191V/I，rtN202S，rtS202S/C，rtS202G，rtS213T，rtV/G214E，rtS219A，rtS219P，rtN/Q238H，rtN/S/H238N/K，rtN/S/H/T238/T/A/S/L，rtR242R/K，rtR242R/S，rtN248H，rtI253A，s118-207，s117-120DEL，sI68I/M，sC69F/L，sL109I/L，sG112R，sS17T，sT118R，sK122R，sT123P，sT126S，sT131N，sN131T，sM133K/M，sM133I，sY/F134S，sC139C/G，sK141E，sD144E，sG145R，rtT128T/I，rtL82M，rtT135C，rtT150A，rtV163I，rtT184S，rtA200V，rtF202V，rtS213T，rtQ215H，rtS219A，rtA222T，rtI224S，rtL229M，rtL235I，rtN238S，rtS78T，rt116DEL122，rtI163V，rtL180V，rtE8A，rtV23I，rtD31D/G，rtY53D，rtV58V/I，rtA/S21T，rtV/I/N/S/T53D，rtV/I/N/S/T53Y，rtS/T/N/H/A54Y/H，PreS2 L11L/A，PreS2 R171，DEL PreS2 18-21，PreS2 T30A，PreS2 N54H，sT13T/A，PreS2 Q1V，PreS2 Q1M，rtH90D，rtL/F108L，rtL157L/M，rtA181V，rt207I，rtP109S，rtN/H/A/S/Q238K，s181M，sP214Q，sF83S，sL173F，sW199L，sI126T，sK160R，sS174N，sA84V，sS210N，sC69STOP/C，sC76Y，si110V/I，sY134N，sW172STOP/W，K32M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；N33D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；P34S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；H35I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；T37W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P59S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；K60M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；F61P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；A62R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；V63A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；D83C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/缺失；V84A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；S85T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；A86R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Y89V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；H90I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；I/L91K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/缺失；P177S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；F178P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；L179K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；L180K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；A181R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Q183E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；F183P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；T184W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；Y203V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；M204F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；L235K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N236D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；T237W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P237S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；
N238D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H238I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；A238R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；8239T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；Q238E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；K239M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；L247K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N248D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H248I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；F249P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；M250F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；G251H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/缺失；和V251A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；(b)機(jī)器可讀數(shù)據(jù)存儲(chǔ)介質(zhì)，包括用機(jī)器可讀數(shù)據(jù)編碼的數(shù)據(jù)存儲(chǔ)材料，其中數(shù)據(jù)包括分子或分子復(fù)合物的原子坐標(biāo)；(c)工作存儲(chǔ)器，用于存儲(chǔ)處理(a)和(b)的機(jī)器可讀數(shù)據(jù)的指令；(d)連接于工作存儲(chǔ)器和(a)和(b)的機(jī)器可讀數(shù)據(jù)存儲(chǔ)介質(zhì)的中央處理單元，用于進(jìn)行(a)的機(jī)器可讀數(shù)據(jù)的轉(zhuǎn)換和用于將(b)的機(jī)器可讀數(shù)據(jù)處理成結(jié)構(gòu)坐標(biāo)；和(e)連接于中央處理單元的顯示器，用于顯示分子或分子復(fù)合物的結(jié)構(gòu)坐標(biāo)。
本發(fā)明的另一方面提供了使用編程的計(jì)算機(jī)來(lái)鑒定藥劑的計(jì)算機(jī)輔助方法，該藥劑潛在地能夠結(jié)合HBV聚合酶的結(jié)構(gòu)域，并任選地調(diào)節(jié)HBV聚合酶的至少一種功能活性，該方法包括步驟(a)將數(shù)據(jù)輸入編程的計(jì)算機(jī)中，數(shù)據(jù)包括HBV聚合酶r t或其片段在位置28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257和/或在位置編號(hào)4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266的原子坐標(biāo)；(b)使用計(jì)算機(jī)方法，產(chǎn)生與(a)中限定的原子坐標(biāo)具有立體化學(xué)互補(bǔ)性結(jié)構(gòu)的一套原子坐標(biāo)或其子集，由此產(chǎn)生標(biāo)準(zhǔn)數(shù)據(jù)集；(c)使用處理器，將標(biāo)準(zhǔn)數(shù)據(jù)集包括于化學(xué)結(jié)構(gòu)的計(jì)算機(jī)數(shù)據(jù)庫(kù)；(d)使用計(jì)算機(jī)方法，從數(shù)據(jù)庫(kù)中選擇與所述標(biāo)準(zhǔn)數(shù)據(jù)集的部分相似的化學(xué)結(jié)構(gòu)；和(e)輸出所選擇的與標(biāo)準(zhǔn)數(shù)據(jù)集的部分相似的化學(xué)結(jié)構(gòu)。
另一方面，本發(fā)明涉及藥劑的鑒定，該藥劑能夠與HBV聚合酶或其片段相互作用且任選地下調(diào)與所述HBV聚合酶相關(guān)的至少一種功能活性，其中所述HBV聚合酶具有至少一種以下的特征(i)和天然HBV聚合酶相比，顯示對(duì)核苷類似物(如ADV、LMV、FCV、FTC、ETV、TDF、DAPD和DXG)提高的抗性或降低的敏感度；(i)包括選自氨基酸殘基28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257，或4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266區(qū)域中的突變，諸如但不限于rtA21S，rtA38E，rtY54H，rtN76D，rtL91I，rtF122L，rtY124H，rtT128N，rtQ130P，rtT184G，rtM204V/I，rtS202I，rtH248N，rtY252L，rtS21A，rtN/S/T/I/V53D，rtY54H，rtS57P，rtL91I，rtS116P，rtL122F，rtF122L，rtN124H，rtY124H，rtH126R，rtY126Q，rtT128N，rtP130Q，rtD131N，rtV134D，rtY135C，rtY141Y/F，rtL145M，rtF151T/F，rtL180M，rtA181T，rtS202G，rtI204V，rtK212R，rtL217R，rtS219A，rtI235I/M，rtN236T，rtN238D，sP120T，sM125T，sS126T，sT127A，sT118R，sM133L/M，sM133T，sF134V，sS143S/T，sD144A，sG145A，sW172Stop，sI195M，sS207R，sY225Y/C，間隔基L97I，間隔基K115R，間隔基H116L，間隔基L128F，間隔基S137G，間隔基R139G，間隔基F142S，rtA97V，rtH126R，rtS135Y，rtM204I，PreS1 N114D，PreS1 T115S，PreS2 F22L，PreS2 V39A，PreS2 P52L，sL89V，sT118A，sF161L，sE164D，sI195M，sI208T，PreS1 E86Q，PreS1 N91K，PreS2 P41H，sQ30K，sP120T，sL176V，sV194F，rtS21A，rtL122F，rtN124H，rtH126R，rtP130Q，rtD131N，rtY135C，rtN/S/T/I/V53D，rtY126Q，rtS202G，rtI204V，rtI235I/M，sM125T，sT127A，sT118R，sM133T，sF134V，sI195M，sS207R，sY225Y/C，rtG172E，rtG174C，rtP177L，rtL180V，rtT184S，sR160N，sE164D，sF170L，sL175L/S，sQ181E/G/Q，sC/W182Y/STOP，sW196L，sW196S，sW196STOP，sM198I，sW199S，sS204T，sY206N，sS210K，sS210R，sL216STOP，sY255F，rtL77L/F，rtL77L/M/V，rtL80I，rtL80V，rtH90N/H，rtS117S/Y，rt125DELrt128，rtQ125K，rtQ125N，rtY126Q，rtL128L/M，rtT128A，rtL132L/M，rtN134G，rtS137T，rtN139H，rtN139K，rtY141Y/STOP，rtV/G142L，rtL147L/W，rtK149R，rtG153E，rtR153Q，rtW153S，rtW153Q，rtF166L，rtI169L，rtF178F/L，rtI187L，rtI187I/V，rtV191I，rtV191V/I，rtN202S，rtS202S/C，rtS202G，rtS213T，rtV/G214E，rtS219A，rtS219P，rtN/Q238H，rtN/S/H238N/K，rtN/S/H/T238/T/A/S/L，rtR242R/K，rtR242R/S，rtN248H，rtI253A，s118-207，s117-120DEL，sI68I/M，sC69F/L，sL109I/L，sG112R，sS17T，sT118R，sK122R，sT123P，sT126S，sT131N，sN131T，sM133K/M，sM133I，sY/F134S，sC139C/G，sK141E，sD144E，sG145R，rtT128T/I，rtL82M，rtT135C，rtT150A，rtV163I，rtT184S，rtA200V，rtF202V，rtS213T，rtQ215H，rtS219A，rtA222T，rtI224S，rtL229M，rtL235I，rtN238S，rtS78T，rt116DEL122，rtI163V，rtL180V，rtE8A，rtV23I，rtD31D/G，rtY53D，rtV58V/I，rtA/S21T，rtV/I/N/S/T53D，rtV/I/N/S/T53Y，rtS/T/N/H/A54Y/H，PreS2L11L/A，PreS2 R17I，DEL PreS2 18-21，PreS2 T30A，PreS2 N54H，sT13T/A，PreS2 Q1V，PreS2 Q1M，rtH90D，rtL/F108L，rtL157L/M，rtA181V，rtV207I，rtP109S，rtN/H/A/S/Q238K，s181M，sP214Q，sF83S，sL173F，sW199L，sI126T，sK160R，sS174N，sA84V，sS210N，sC69STOP/C，sC76Y，si110V/I，sY134N，sW172STOP/W，K32M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；N33D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；P34S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；H35I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；T37W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P59S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；
K60M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；F61P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；A62R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；V63A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；D83C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/缺失；V84A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；S85T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；A86R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Y89V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；H90I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；I/L91K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/缺失；P177S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；F178P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；L179K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；L180K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；A181R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Q183E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；F183P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；T184W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；Y203V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；M204F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；L235K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N236D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；T237W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P237S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；N238D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H238I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；A238R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；S239T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；Q238E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；K239M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；L247K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；
N248D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H248I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；F249P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；M250F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；G251H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/缺失；和V251A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；和/或(ii)包括SEQ ID NO1中所述的氨基酸序列或限定HBV聚合酶且在與SEQ ID NO1最佳比對(duì)后具有至少70％相似性序列的氨基酸序列。
所述方法包括將所述HBV聚合酶與待測(cè)試的藥劑接觸并測(cè)定所述藥劑與所述HBV聚合酶相互作用的互補(bǔ)性程度。
特別優(yōu)選的實(shí)施方案中，本發(fā)明的方法涉及藥劑的鑒定，如核苷類似物，其結(jié)合核苷抗性HBV聚合酶分子的核苷酸結(jié)合口袋，或聚合酶的其它區(qū)域，以此改變聚合酶活性，以及涉及因此鑒定的藥劑。這些可以用作治療劑或診斷劑。本發(fā)明方法進(jìn)一步提供了對(duì)HBV聚合酶rt結(jié)構(gòu)域其它部分的抗性作圖的能力。
優(yōu)選地，藥劑可以結(jié)合HBV聚合酶的核苷酸結(jié)合口袋。
另一優(yōu)選實(shí)施方案中，通過(guò)抑制HBV的復(fù)制來(lái)測(cè)量功能活性。
另一優(yōu)選實(shí)施方案中，鑒定了HBV聚合酶結(jié)構(gòu)中三個(gè)潛在的具有組氨酸和半胱氨酸殘基簇的金屬結(jié)合區(qū)域。這些新的結(jié)合位點(diǎn)可能涉及聚合酶活性或相關(guān)的功能如RNA/DNA結(jié)合或新延伸鏈的鏈轉(zhuǎn)換。
本發(fā)明的再一方面，HBV聚合酶中三個(gè)另外的金屬結(jié)合位點(diǎn)并涉及藥劑的鑒定，該藥劑結(jié)合HBV聚合酶分子中的金屬結(jié)合位點(diǎn)，來(lái)改變聚合酶活性，以及涉及因此鑒定的藥劑。這些可以用作治療劑或診斷劑。本發(fā)明方法進(jìn)一步提供了對(duì)包括這三個(gè)金屬結(jié)合位點(diǎn)的HBV聚合酶rt結(jié)構(gòu)域其它部分的抗性作圖的能力。
本發(fā)明的再一方面，涉及利用在此所述方法所鑒定的藥劑來(lái)調(diào)節(jié)野生型或抗病毒藥物抗性HBV聚合酶活性的用途，尤其是，這些藥劑在治療和/或預(yù)防治療HBV感染中的用途。與HBV聚合酶相互作用的其它藥劑可以用作診斷劑。
本發(fā)明的再一方面提供了調(diào)節(jié)至少一種與HBV聚合酶相關(guān)的功能活性的方法，所述方法包括將有效量的根據(jù)在此所限定方法鑒定的藥劑，在足以使所述藥劑與所述HBV聚合酶分子相互作用并抑制或降低聚合酶活性的條件下引入所述患者中一段時(shí)間。
優(yōu)選地，該藥劑抑制HBV的復(fù)制。
應(yīng)當(dāng)理解本發(fā)明的這個(gè)方面包括體內(nèi)治療以及調(diào)節(jié)體外培養(yǎng)系統(tǒng)中HBV聚合酶活性的兩者。例如當(dāng)篩選具有HBV聚合酶拮抗活性的藥劑時(shí)，后者是有利的。
再一方面中，本發(fā)明涉及治療和/或預(yù)防HBV感染的方法，所述方法包括將有效量的根據(jù)在此限定方法鑒定的能夠調(diào)節(jié)所述HBV的HBV聚合酶的藥劑，在足以使所述藥劑與所述HBV聚合酶分子相互作用并抑制或降低聚合酶活性的條件下給藥于患者一段時(shí)間。
優(yōu)選實(shí)施方案中，預(yù)防或治療的患者是哺乳動(dòng)物，更優(yōu)選為人。
另一方面，本發(fā)明涉及能夠調(diào)節(jié)至少一種與HBV聚合酶相關(guān)的功能活性的藥劑在制造用于治療和/或預(yù)防患者HBV感染藥物中的用途，該藥劑是根據(jù)在此所限定方法鑒定的。
本發(fā)明的再一方面，涉及包括抑制或降低HBV聚合酶活性的藥劑的藥物組合物。這樣的組合物通常進(jìn)一步包括一種或多種藥物學(xué)上可接受的載體和/或稀釋劑。
還應(yīng)當(dāng)理解本發(fā)明擴(kuò)展至HBV聚合酶或其結(jié)構(gòu)域的三維結(jié)構(gòu)坐標(biāo)在分析和/或闡述HBV核酸復(fù)制機(jī)理中的用途。本發(fā)明進(jìn)一步擴(kuò)展至由其衍生的診斷、治療和/或預(yù)防發(fā)展。
仍然進(jìn)一步應(yīng)當(dāng)理解本發(fā)明擴(kuò)展至任何非天然產(chǎn)生形式的HBV聚合酶分子。HBV聚合酶分子的非天然產(chǎn)生形式的實(shí)例特別包括分子的結(jié)晶形式。
本發(fā)明進(jìn)一步能夠預(yù)測(cè)抑制來(lái)自特定分離物HBV聚合酶的可能性或其它方面。
表1提供了貫穿本說(shuō)明書(shū)中所用的序列識(shí)別符匯總。
表1序列識(shí)別符的匯總
表2 提供了貫穿說(shuō)明書(shū)中所用的單個(gè)或三個(gè)字母的縮寫(xiě)。
表2單個(gè)或三個(gè)氨基酸的縮寫(xiě)
表3 提供了在此所用縮寫(xiě)的列表。
表3縮寫(xiě)
附圖簡(jiǎn)述圖1是顯示了抗性突變的HBV和HIV的比對(duì)。如果需要可從申請(qǐng)者處獲得該圖的彩色版。
圖2是HBV聚合酶同系物模型的照片圖像，顯示了基于HI V逆轉(zhuǎn)錄酶的結(jié)構(gòu)域。該模型是基于晶體結(jié)構(gòu)1RTD(Das等，Jounal ofVirlogy 754771-4779，2001)和HBV與HIV聚合酶蛋白質(zhì)的比對(duì)(圖1)來(lái)構(gòu)建的。結(jié)構(gòu)上保守的結(jié)構(gòu)域是高光的；結(jié)構(gòu)域F(紅色)，A(橙色)，B(黃色)，C(綠色)，D(白色)和E(粉色)。DNA的模板和引物鏈顯示為藍(lán)色和綠色。存在于催化位點(diǎn)的鎂離子顯示為紫色。三個(gè)推定的金屬結(jié)合位點(diǎn)顯示為灰色。如果需要可從申請(qǐng)者那獲得該圖的彩色版本。
圖3是顯示了基序F和G結(jié)構(gòu)域的圖像。
圖4是結(jié)構(gòu)圖像，顯示了與LMV結(jié)合的HBV雙突變r(jià)tM204V/rtL180M的結(jié)合位點(diǎn)。提出殘基180的突變改變r(jià)tF188的構(gòu)象并導(dǎo)致與LNV不理想的立體相互作用。如果需要可從申請(qǐng)者那獲得該圖的彩色版本。
圖5是結(jié)構(gòu)圖像，顯示了天然HBV(綠色)和HBV突變V173L(白色)與LMV結(jié)合的結(jié)合位點(diǎn)，顯示了rtL173和rtF88突變之間的接近，在位置173旋轉(zhuǎn)F88的芳環(huán)導(dǎo)致其侵占結(jié)合口袋來(lái)阻斷LMV的結(jié)合。如果需要可從申請(qǐng)者那獲得該圖的彩色版本。
圖6是結(jié)構(gòu)圖像，顯示了帶有ADV和鎂離子(紫色)的天然HBV的結(jié)合位點(diǎn)模型，顯示了殘基rtN236與S85和活性位點(diǎn)的接近(3.4_)。如果需要可從申請(qǐng)者那獲得該圖的彩色版本。
圖7是系統(tǒng)的圖示，該系統(tǒng)用于進(jìn)行存儲(chǔ)介質(zhì)編碼的指令。
圖8是磁性存儲(chǔ)介質(zhì)的橫截面圖示。
圖9是光學(xué)可讀數(shù)據(jù)存儲(chǔ)系統(tǒng)橫的截面圖示。
圖10是結(jié)構(gòu)圖像，顯示了涉及LMV抗性的位置80的亮氨酸至異亮氨酸的突變。如果需要可從申請(qǐng)者那獲得該圖的彩色版本。
圖11是結(jié)構(gòu)圖像，顯示了導(dǎo)致LMV抗性的位置173的纈氨酸至亮氨酸的突變。如果需要可從申請(qǐng)者那獲得該圖的彩色版本。
圖12是結(jié)構(gòu)圖像，顯示了導(dǎo)致ADV抗性的位置181的丙氨酸至蘇氨酸的突變。
圖13是結(jié)構(gòu)圖像，顯示了導(dǎo)致ADV抗性的位置236的天冬酰胺至蘇氨酸的突變。
圖14是結(jié)構(gòu)圖像，顯示了導(dǎo)致恩替卡韋抗性的位置38的丙氨酸至谷氨酸的突變。
圖15是結(jié)構(gòu)圖像，顯示了導(dǎo)致恩替卡韋抗性的位置202的絲氨酸至異亮氨酸的突變。
圖16是氨基酸序列的比對(duì)，顯示核苷和核苷酸類似物的一級(jí)和二級(jí)突變結(jié)合位點(diǎn)。
圖17是結(jié)構(gòu)圖像，顯示提出的金屬結(jié)合位點(diǎn)1。形成位點(diǎn)的殘基是rtE1、rtH12、rtH13、rtH160和rtA162。
圖18是結(jié)構(gòu)圖像，顯示提出的金屬結(jié)合位點(diǎn)2。形成位點(diǎn)的殘基是rtC-9、rtH-6、rtH90、rtL93和rtH234。
圖19是結(jié)構(gòu)圖像，顯示提出的金屬結(jié)合位點(diǎn)3。形成位點(diǎn)的殘基是rtH197、rtC198、rtH216和rtC213。
圖20是DNA印跡的表示，顯示了用ADV(0、0.1、0.5、1.0、5.0、10μM)或LMV(0、0.001、0.01、0.1、1、10μM)處理的細(xì)胞中檢測(cè)到的HBV復(fù)制中間物。
發(fā)明詳述本發(fā)明提供了野生型HBV聚合酶rt結(jié)構(gòu)域的三級(jí)結(jié)構(gòu)。該結(jié)構(gòu)證明了HBV聚合酶對(duì)于抗病毒藥劑抗性的分子基礎(chǔ)，因此，可以鑒定、篩選、分析、合理設(shè)計(jì)和/或改進(jìn)調(diào)節(jié)HBV聚合酶功能活性的藥劑，尤其是對(duì)ADV、LMV、FCV、FTC、ETV、TDF、DAPD或DXG中的一種或多種或核苷/核苷酸類似物抗性的HBV聚合酶。這些藥劑特別可以用作治療和預(yù)防涉及HBV感染復(fù)制的病癥的激動(dòng)劑或拮抗劑。該藥劑還可以用于診斷目的。
在詳細(xì)描述本發(fā)明之前，應(yīng)當(dāng)理解，除非另外指出，本發(fā)明不受限于制劑的特定劑型、制造方法、給藥方案等等，因此可以改變。還應(yīng)當(dāng)理解在此所用的術(shù)語(yǔ)僅僅是用于描述特定實(shí)施方案的目的，并不是來(lái)限制。
必需注意，如本說(shuō)明書(shū)中所用的，單數(shù)形式“一”、“一個(gè)”和“一種”包括復(fù)數(shù)部分，除非文中另外清楚地表明。因此，例如，引用“一種藥劑”包括單個(gè)藥劑，以及兩種或多種藥劑；“一種核苷類似物”包括單個(gè)類似物，以及兩種或三種類似物；引用“HBV變體”包括兩種或多種HBV變體，等等。
在本發(fā)明的描述和權(quán)利要求中，根據(jù)以下所列的定義來(lái)使用以下術(shù)語(yǔ)。
在此交替使用的術(shù)語(yǔ)“藥劑”、“化合物”、“活性成分”、“藥物學(xué)活性劑”、“藥物”、“活性物”和“藥”指的是誘導(dǎo)所需效果的化學(xué)化合物，如通過(guò)抑制HBV DNA聚合酶活性或功能來(lái)抑制病毒復(fù)制。術(shù)語(yǔ)還包括這些在此特意提及的活性劑的藥物學(xué)上可接受的和藥物學(xué)上活性的成分，包括但不限于鹽、酯、酰胺、前藥、活性代謝物、類似物等等。當(dāng)術(shù)語(yǔ)“藥劑”、“化合物”，“活性成分”、“藥物學(xué)上活性劑”、“藥物”、“活性物”和“藥”使用時(shí)，然后應(yīng)當(dāng)理解為這包括活性劑本身以及藥物學(xué)上可接受的、藥物學(xué)上活性的鹽、酯、酰胺、前藥、代謝物、類似物，等。
因此，本發(fā)明涉及用于抑制HBV DNA聚合酶或與HBV聚合酶相互作用的化合物，如診斷劑。參照核苷類似物如ADV、LMV、FCV、FTC、ETV、TDF、DAPD和/或DXG，包括兩種或多種類似物的組合。
如在此所用的術(shù)語(yǔ)“有效量”和“治療有效量”的藥劑意思是足夠量的藥劑來(lái)提供所需的抑制HBV聚合酶的治療或生理作用或用作診斷劑。此外，“有效HBV-抑制量”或“有效癥狀改善量”的藥劑是足夠量的藥劑來(lái)直接或間接抑制復(fù)制。不理想的作用，例如副作用，有時(shí)與所需的治療效果一起出現(xiàn)；因此，醫(yī)師在決定什么是合適的“有效量”中平衡可能的效果對(duì)可能的風(fēng)險(xiǎn)。實(shí)際所需的量在患者與患者之間是不同的，取決于物種、年齡和患者的一般條件、給藥方式等等。因此，不可能限定實(shí)際的“有效量”。然而，通過(guò)本領(lǐng)域技術(shù)人員僅使用常規(guī)實(shí)驗(yàn)就可以決定任何個(gè)體情況中的合適“有效量”。
“藥物學(xué)上可接受的”載體、賦形劑或稀釋劑意思是由非生物或非其它不理想材料構(gòu)成的藥物學(xué)載體，即材料可以與所選擇的活性劑一起給藥于患者，而沒(méi)有導(dǎo)致任何或?qū)嵸|(zhì)性的不良反應(yīng)。載體可以包括賦形劑和其它添加劑如稀釋劑、去污劑、著色劑、濕潤(rùn)劑或乳化劑、pH緩沖劑、防腐劑，等等。
相似地，如在此提供的化合物的“藥物學(xué)上可接受的”鹽、酯、酰胺、前體藥物或衍生物是非生物或非其它不理想的鹽、酯、酰胺、前體藥物或衍生物。
如在此所用的術(shù)語(yǔ)“醫(yī)治”和“治療”指的是降低與HBV感染相關(guān)癥狀的嚴(yán)重程度和/或頻率，消除癥狀和/或潛在的誘因，預(yù)防癥狀和/或其潛在誘因的發(fā)生，并改善或緩解損害。因此，例如，“治療”患者包括通過(guò)抑制HBV聚合酶來(lái)抑制HBV復(fù)制來(lái)預(yù)防HBV感染以及治療臨床HBV癥狀個(gè)體。因此，例如，這種“治療”HBV感染或傾向發(fā)展的患者的方法包括HBV感染的預(yù)防以及HBV感染或其癥狀的治療。任何情況中，本發(fā)明包括HBV感染的治療或預(yù)防。
如在此所用的“患者”指的是可以從本發(fā)明的制劑和方法中獲益的動(dòng)物，優(yōu)選哺乳動(dòng)物，更優(yōu)選靈長(zhǎng)類，包括低等靈長(zhǎng)類，更優(yōu)選人。與是否是人或非人動(dòng)物無(wú)關(guān)，患者可以稱為個(gè)體、患者、動(dòng)物、宿主或接受者。本發(fā)明的化合物和方法應(yīng)用于人類醫(yī)藥、獸醫(yī)醫(yī)藥以及通常，馴養(yǎng)或野生動(dòng)物的飼養(yǎng)。為了方便，“動(dòng)物”包括鳥(niǎo)類，如家禽鳥(niǎo)類(包括鴨、雞、火雞和鵝)，飼養(yǎng)場(chǎng)鳥(niǎo)類或野禽。非人動(dòng)物的病癥可以不是天然發(fā)生的HBV感染，而是可以誘導(dǎo)的HBV樣感染。
如上所述，優(yōu)選的動(dòng)物是人，非人靈長(zhǎng)類如狨猴、狒狒、猩猩、低等靈長(zhǎng)類如tupia、家畜、實(shí)驗(yàn)室測(cè)試動(dòng)物、伴生動(dòng)物或被俘的野生動(dòng)物。人是最優(yōu)選的目標(biāo)。然而，可以使用非人動(dòng)物模型。
實(shí)驗(yàn)室測(cè)試動(dòng)物的實(shí)例包括小鼠、大鼠、兔子、豚鼠和倉(cāng)鼠。兔子和嚙齒動(dòng)物如大鼠和小鼠，提供了方便的測(cè)試系統(tǒng)或動(dòng)物模型，靈長(zhǎng)類和低等靈長(zhǎng)類也是如此。家畜包括綿羊、牛、豬、山羊、馬和驢。還包括非哺乳動(dòng)物如鳥(niǎo)類、斑紋魚(yú)(zebrafish)、兩棲動(dòng)物(包括甘蔗蟾蜍(cane toad))和果蠅(Drosophila)屬如黑腹果蠅(Drosophilamelanogaster)。替代活的動(dòng)物模型，測(cè)試系統(tǒng)也包括組織培養(yǎng)系統(tǒng)。
HBV是嗜肝DNA病毒科(hepdnaviridae)的成員，還包括鳥(niǎo)類肝炎病毒如鴨乙型肝炎病毒(DHBV)和哺乳動(dòng)物的肝炎病毒如旱獺肝炎病毒(WHV)。這些病毒與HBV相似并可以用于體外和體內(nèi)或活動(dòng)物模型系統(tǒng)中，來(lái)研究具有對(duì)抗病毒藥物如核苷或核苷酸類似物抗性或降低敏感度的HBV聚合酶。
“抗HBV藥物”包括核苷或核苷酸類似物、蛋白質(zhì)或化合物。
本發(fā)明涉及鑒定藥劑的方法，該藥劑能夠與HBV聚合酶相互作用并優(yōu)選調(diào)節(jié)至少一種與所述HBV聚合酶相關(guān)的功能活性，所述方法包括將所述HBV聚合酶與待測(cè)試藥劑接觸并測(cè)定所述藥劑與所述聚合酶相互作用的互補(bǔ)性程度。
HBV聚合酶也可以稱為“pol”。HBV基因組中最大的開(kāi)放閱讀框(ORF)編碼HBV聚合酶。P01大小為90kd并具有RNA和DNA依賴性聚合酶活性(Toh等，Nature 305827-829，1983)。Pol在HBV基因組世代以及pgRNA殼體化中起關(guān)鍵作用。Pol在HBV病毒粒子中與pgRNA一起得到包裝(Mack等，J.Virol.624786-4790，1988)。
將HBV聚合酶分成四個(gè)特征化的結(jié)構(gòu)域。基于序列同源性和對(duì)病毒基因組復(fù)制機(jī)理的研究，大部分pol是必不可少的。蛋白質(zhì)的N-端部分啟動(dòng)(-)DNA鏈合成并終止于共價(jià)連接(-)DNA鏈的5’端。將該結(jié)構(gòu)域稱為終端蛋白。隨后的結(jié)構(gòu)域沒(méi)有顯示出具有任何酶促功能，但是作為第一個(gè)和第三個(gè)結(jié)構(gòu)域之間的間隔基。第三個(gè)結(jié)構(gòu)域具有逆轉(zhuǎn)錄酶的功能。其占據(jù)約40％的蛋白質(zhì)并呈現(xiàn)出RNA和DNA依賴性聚合酶活性(Lanford等，J.Virol.731885-1893，1999)。然而，pol還需要金屬離子的存在和莖環(huán)的存在用于產(chǎn)生聚合酶/rt活性(Urban等，J.Gen.Virol.791121-1131，1998；Bartenschlager和Schaller，EMBO J.74185-4192，1992；Tavis等，J.Virol.725789-5796，1998)。第四個(gè)結(jié)構(gòu)域具有RNA酶H活性(Chang等，Proc.Natl.Acad Sci.USA875158-5162，1990；Radziwill等，J.Virol.64613-620，1990)。該結(jié)構(gòu)域還在HBV基因組復(fù)制中起關(guān)鍵作用。
HBV聚合酶還含有許多與其它RNA依賴性聚合酶同源的區(qū)域(Poch等，European Molecular Biology Organisation 83867-3874，1989；Lesburg等，Nat.Struct.Biol.6(10)937-943，1999)。將這些區(qū)域命名為結(jié)構(gòu)域A-G，其中最近命名的結(jié)構(gòu)域F和G是在推斷的蛋白質(zhì)序列中的結(jié)構(gòu)域A之前(Lesburg，1999，上述)。在其它逆轉(zhuǎn)錄酶蛋白質(zhì)中，結(jié)構(gòu)F此前稱為基序2，而結(jié)構(gòu)域G是基序1(Nakamura等，Science 277955-959，1997；Xiong和Eickbush，EMBO J.9(10)3353-3362，1990)。Stuyver等，2001，出處同前，發(fā)展了通用編號(hào)系統(tǒng)來(lái)提供一致的氨基酸編號(hào)系統(tǒng)用于HBV聚合酶蛋白質(zhì)。該系統(tǒng)中，將YMDD基序中的甲硫氨酸(使用單個(gè)氨基酸命名)指定為殘基204(之前的密碼子539、550或552；表4)。此外，聚合酶四個(gè)功能區(qū)域中的每個(gè)(終端蛋白質(zhì)、間隔基、逆轉(zhuǎn)錄酶和RNA酶H)各自編號(hào)。
表4HBV聚合酶公認(rèn)的結(jié)構(gòu)域特異性編號(hào)系統(tǒng)，RT結(jié)構(gòu)域，改編自Stuyver等，2001，出處同前
本發(fā)明包括HBV聚合酶對(duì)其可變?yōu)榭剐缘目共《舅幬铮鏊幬锇ǖ幌抻诤塑疹愃莆锼幬?，如ADV、LMV、FCV、FTC、ETV、DAPD和DXG。
測(cè)定作用于HBV聚合酶的藥物活性的非限制性實(shí)例包括測(cè)定對(duì)藥物抗性的水平，包括測(cè)定抗病毒藥物在感染HBV患者中的臨床活性；抗病毒藥物抑制細(xì)胞培養(yǎng)物中病毒復(fù)制的能力；體外測(cè)量抗病毒藥劑和病毒聚合酶之間的Km值(Das等，2001，出處同前)；和抗病毒藥劑和病毒聚合酶之間的相互作用，使用在計(jì)算機(jī)芯片上(in-silico)建模(Das等，2001，出處同前)。
抗病毒藥劑抗性的HBV聚合酶包括在抗病毒藥物存在下保持功能活性的HBV聚合酶。優(yōu)選的抗病毒藥物是核苷類似物如ADV、LMV、FCV、FTC、ETV、TDF、DAPD和DXG。為了本發(fā)明的目的，術(shù)語(yǔ)“天然HBV聚合酶”理解為對(duì)核苷類似物失活敏感的HBV聚合酶。
由于核糖部分3’-羥基的缺失，核苷逆轉(zhuǎn)錄酶抑制劑(NRTI)也是核苷類似物或二脫氧核苷類似物的實(shí)例。作為內(nèi)源核苷，核苷類似物必須三磷酸化成核苷酸。起初，核苷類似物生物轉(zhuǎn)化需要酶，如胸苷激酶、脫氧胞苷激酶和肌苷磷酸轉(zhuǎn)移酶來(lái)形成單磷酸代謝物。一旦成為三磷酸化的形式，二脫氧核苷酸可以與天然形成的核苷酸競(jìng)爭(zhēng)用于DNA摻入。二脫氧核苷酸將結(jié)合在逆轉(zhuǎn)錄酶上并使其摻入延伸的病毒互補(bǔ)DNA(cDNA)中。這些核苷/核苷酸的核糖部分上的3’-羥基的缺失導(dǎo)致DNA延伸終止。
抗病毒藥物抗性HBV聚合酶通常包括一個(gè)或多個(gè)以下的特征(i)和天然HBV聚合酶相比較，對(duì)核苷類似物如ADV、LMV、FCV、FTC、ETV、TDF、DAPD和DXG呈現(xiàn)提高的抗性或降低的敏感度；(ii)包括選自氨基酸殘基28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257，或4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266區(qū)域內(nèi)的突變，諸如但不限于rtA21S，rtA38E，rtY54H，rtN76D，rtL91I，rtF122L，rtY124H，rtT128N，rtQ130P，rtT184G，rtM204V/I，rtS202I，rtH248N，rtY252L，rtS21A，rtN/S/T/I/V53D，rtY54H，rtS57P，rtL91I，rtS116P，rtL122F，rtF122L，rtN124H，rtY124H，rtH126R，rtY126Q，rtT128N，rtP130Q，rtD131N，rtV134D，rtY135C，rtY141Y/F，rtL145M，rtF151T/F，rtL180M，rtA181T，rtS202G，rtI204V，rtK212R，rtL217R，rtS219A，rtI235I/M，rtN236T，rtN238D，sP120T，sM125T，sS126T，sT127A，sT118R，sM133L/M，sM133T，sF134V，sS143S/T，sD144A，sG145A，sW172Stop，sI195M，sS207R，sY225Y/C，間隔基L97I，間隔基K115R，間隔基H116L，間隔基L128F，間隔基S137G，間隔基R139G，間隔基F142S，rtA97V，rtH126R，rtS 135Y，rtM204I，PreS1 N114D，PreS1 T115S，PreS2 F22L，PreS2 V39A，PreS2 P52L，sL89V，sT118A，sF161L，sE164D，sI195M，sI208T，PreS1E86Q，PreS1N91K，PreS2P41H，sQ30K，sP120T，sL176V，sV194F，rtS21A，rtL122F，rtN124H，rtH126R，rtP130Q，rt131N，rtY135C，rtN/S/T/I/V53D，rtY126Q，rtS202G，rtI204V，rtI235I/M，sM125T，sT127A，sT118R，sM133T，sF134V，sI195M，sS207R，sY225Y/C，rtG172E，rtG174C，rtP177L，rtL180V，rtT184S，sR160N，sE164D，sF170L，sL175L/S，sQ181E/G/Q，sC/W182Y/STOP，sW196L，sW196S，sW196STOP，sM198I，sW199S，sS204T，sY206N，sS210K，sS210R，sL216STOP，sY255F，rtL77L/F，rtL77L/M/V，rtL80I，rtL80V，rtH90N/H，rtS117S/Y，rt125DELrt128，rtQ125K，rtQ125N，rtY126Q，rtL128L/M，rtT128A，rtL132L/M，rtN134G，rtS 137T，rtN139H，rtN139K，rtY141Y/STOP，rtV/G142L，rtL147L/W，rtK149R，rtG153E，rtR153Q，rtW153S，rtW153Q，rtF166L，rtI169L，rtF178F/L，rtI187L，rtI187I/V，rtV191I，rtV191V/I，rtN202S，rtS202S/C，rtS202G，rtS213T，rtV/G214E，rtS219A，rtS219P，rtN/Q238H，rtN/S/H238N/K，rtN/S/H/T238/T/A/S/L，rtR242R/K，rtR242R/S，rtN248H，rtI253A，s118-207，s117-120DEL，sI68I/M，sC69F/L，sL109I/L，sG112R，sS17T，sT118R，sK122R，sT123P，sT126S，sT131N，sN131T，sM133K/M，sM133I，sY/F134S，sC139C/G，sK141E，sD144E，sG145R，rtT128T/I，rtL82M，rtT135C，rtT150A，rtV163I，rtT184S，rtA200V，rtF202V，rtS213T，rtQ215H，rtS219A，rtA222T，rtI224S，rtL229M，rtL235I，rtN238S，rtS78T，rt116DEL122，rtI163V，rtL180V，rtE8A，rtV23I，rtD31D/G，rtY53D，rtV58V/I，rtA/S21T，rtV/I/N/S/T53D，rtV/I/N/S/T53Y，rtS/T/N/H/A54Y/H，PreS2L11L/A，PreS2 R17I，DEL PreS2 18-21，PreS2 T30A，PreS2 N54H，sT13T/A，PreS2 Q1V，PreS2 Q1M，rtH90D，rtL/F108L，rtL157L/M，rtA181V，rtV207I，rtP109S，rtN/H/A/S/Q238K，s181M，sP214Q，sF83S，sL173F，sW199L，sI126T，sK160R，sS174N，sA84V，sS210N，sC69STOP/C，sC76Y，si110V/I，sY134N，sW172STOP/W，K32M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；N33D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；P34S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；H35I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；T37W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P59S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；K60M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；F61P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；
A62R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；V63A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；D83C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/缺失；V84A/R/N/D/C/Q/E/G/H/I/L/M/M/F/P/S/T/W/Y/缺失；S85T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；A86R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Y89V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；H90I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；I/L91K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/缺失；P177S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；F178P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；L179K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；L180K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；A181R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Q183E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；F183P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；T184W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；Y203V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；M204F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；L235K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N236D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；T237W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P237S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；N238D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H238I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；A238R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；S239T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；Q238E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；K239M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；L247K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N248D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H248I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；
F249P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；M250F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；G251H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/缺失；和V251A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；和/或(iii)包括SEQ ID NO1中所述的氨基酸序列或限定HBV聚合酶且在與SEQ ID NO1最佳比對(duì)后具有至少70％相似性序列的氨基酸序列。
參照“至少70％相似性”包括70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99或100％的相似性。
其上多種突變已經(jīng)作圖的野生型HBV聚合酶rt結(jié)構(gòu)域原子坐標(biāo)列于表6中。本發(fā)明拓寬至對(duì)任何其它藥物如核苷或核苷酸類似物抗性的HBV聚合酶的坐標(biāo)。
在此涉及的各種HBV聚合酶包括野生型HBV聚合酶以及變體聚合酶，諸如那些攜帶選自氨基酸殘基區(qū)域28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257，或4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266內(nèi)的突變，諸如但不限于 rtA21S，rtA38E，rtY54H，rtN76D，rtL91I，rtF122L，rtY124H，rtT128N，rtQ130P，rtT184G，rtM204V/I，rtS202I，rtH248N，rtY252L，rtS21A，rtN/S/T/I/V53D，rtY54H，rtS57P，rtL91I，rtS116P，rtL122F，rtF122L，rtN124H，rtY124H，rtH126R，rtY126Q，rtT128N，rtP130Q，rtD131N，rtV134D，rtY135C，rtY141Y/F，rtL145M，rtF151T/F，rtL180M，rtA181T，rtS202G，rtI204V，rtK212R，rtL217R，rtS219A，rtI235I/M，rtN236T，rtN238D，sP120T，sM125T，sS126T，sT127A，sT118R，sM133L/M，sM133T，sF134V，sS143S/T，sD144A，sG145A，sW172Stop，sI195M，sS207R，sY225Y/C，間隔基L97I，間隔基K115R，間隔基H116L，間隔基L128F，間隔基S137G，間隔基R139G，間隔基F142S，rtA97V，rtH126R，rtS135Y，rtM204I，PreS 1N114D，PreS 1T115S，PreS2 F22L，PreS2 V39A，PreS2 P52L，sL89V，sT118A，sF161L，sE164D，sI195M，sI208T，PreS1 E86Q，PreS1 N91K，PreS2 P41H，sQ30K，sP120T，sL176V，sV194F，rtS21A，rtL122F，rtN124H，rtH126R，rtP130Q，rtD131N，rtY135C，rtN/S/T/I/V53D，rtY126Q，rtS202G，rtI204V，rtI235I/M，sM125T，sT127A，sT118R，sM133T，sF134V，sI195M，sS207R，sY225Y/C，rtG172E，rtG174C，rtP177L，rtL180V，rtT184S，sR160N，sE164D，sF170L，sL175L/S，sQ181E/G/Q，sC/W182Y/STOP，sW196L，sW196S，sW196STOP，sM198I，sW199S，sS204T，sY206N，sS210K，sS210R，sL216STOP，sY255F，rtL77L/F，rtL77L/M/V，rtL80I，rtL80V，rtH90N/H，rtS117S/Y，rt125DELrt128，rtQ125K，rtQ125N，rtY126Q，rtL128L/M，rtT128A，rtL132L/M，rtN134G，rtS137T，rtN139H，rtN139K，rtY141Y/STOP，rtV/G142L，rtL147L/W，rtK149R，rtG153E，rtR153Q，rtW153S，rtW153Q，rtF166L，rtI169L，rtF178F/L，rtI187L，rtI187I/V，rtV191I，rtV191V/I，rtN202S，rtS202S/C，rtS202G，rtS213T，rtV/G214E，rtS219A，rtS219P，rtN/Q238H，rtN/S/H238N/K，rtN/S/H/T238/T/A/S/L，rtR242R/K，rtR242R/S，rtN248H，rtI253A，s118-207，s117-120DEL，sI68I/M，sC69F/L，sL109I/L，sG112R，sS17T，sT118R，sK122R，sT123P，sT126S，sT131N，sN131T，sM133K/M，sM133I，sY/F134S，sC139C/G，sK141E，sD144E，sG145R，rtT128T/I，rtL82M，rtT135C，rtT150A，rtV163I，rtT184S，rtA200V，rtF202V，rtS213T，rtQ215H，rtS219A，rtA222T，rtI224S，rtL229M，rtL235I，rtN238S，rtS78T，rt116DEL122，rtI163V，rtL180V，rtE8A，rtV23I，rtD31D/G，rtY53D，rtV58V/I，rtA/S21T，rtV/I/N/S/T53D，rtV/I/N/S/T53Y，rtS/T/N/H/A54Y/H，PreS2L11L/A，PreS2R17I，DELPreS2 18-21，PreS2 T30A，PreS2 N54H，sT13T/A，PreS2 Q1V，PreS2 Q1M，rtH90D，rtL/F108L，rtL157L/M，rtA81V，rtV207I，rtP109S，rtN/H/A/S/Q238K，s181M，sP214Q，sF83S，sL173F，sW199L，sI126T，sK160R，sS174N，sA84V，sS210N，sC69STOP/C，sC76Y，si110V/I，sY134N，sW172STOP/W，K32M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；N33D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；
P34S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；H35I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；T37W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P59S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；K60M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；F61P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；A62R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；V63A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；D83C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/缺失；V84A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；S85T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；A86R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/YV/缺失；Y89V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；H90I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；I/L91K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/缺失；P177S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；F178P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；L179K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；L180K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；A181R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Q183E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；F183P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；T184W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；Y203V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；M204F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；L235K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N236D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；T237W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P237S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；N238D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H238I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；A238R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；S239T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；Q238E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；
K239M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；L247K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N248D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H248I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；F249P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；M250F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；G251H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/缺失；和/或V251A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；本發(fā)明進(jìn)一步鑒定了HBV聚合酶中涉及核苷或核苷酸類似物結(jié)合的一級(jí)和二級(jí)氨基酸殘基。一級(jí)殘基位于位置編號(hào)28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257。二級(jí)殘基位于位置編號(hào)4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266。
本發(fā)明進(jìn)一步鑒定了三個(gè)新的金屬結(jié)合位點(diǎn)。聚合酶分子需要金屬離子來(lái)催化。除了已知的金屬結(jié)合區(qū)域(我們模型中的殘基205和206)，鑒定了三個(gè)含有組氨酸和酪氨酸殘基簇的區(qū)域。提出的金屬結(jié)合位點(diǎn)1包括殘基rtE1、rtH12、rtH13、rtH160和rtA162。提出的金屬結(jié)合位點(diǎn)2包括殘基rtC-9、rtH-6、rtH90、rtL93和rtH234。提出的金屬結(jié)合位點(diǎn)3包括殘基rtH197、rtC198、rtH216和rtC213。這些另外的HBV聚合酶的金屬結(jié)合位點(diǎn)之前還沒(méi)有得到鑒定，且可以作為抗病毒化合物的靶點(diǎn)。
應(yīng)當(dāng)理解本發(fā)明與推定藥劑接觸來(lái)評(píng)價(jià)相互作用互補(bǔ)性的HBV聚合酶，可以是天然產(chǎn)生形式的蛋白質(zhì)或可以是重組或合成產(chǎn)生的。然而，還應(yīng)當(dāng)理解該蛋白質(zhì)可以采用圖像的形式，如電子密度圖、分子模型(包括但不限于棒、球和棒、填空或表面表示模型)或其它數(shù)碼或非數(shù)碼表示模型或圖像，其有助于利用本領(lǐng)域技術(shù)人員已知的技術(shù)和軟件來(lái)分析所述的HBV聚合酶藥劑相互作用。例如，利用技術(shù)如結(jié)合和解離比例的Biacore實(shí)時(shí)分析和配體結(jié)合的解離常數(shù)來(lái)進(jìn)行相互作用的分析(Gardsvoll等，J.Biol.Chem.274(53)37995-38003，1999；Hoyer-Hansen等，F(xiàn)EBS Lett.420(1)79-85，1997；Ploug，Biochemistry 37(47)16494-16505，1998；Ploug等，Biochemistry33(30)8991-8997，1994；Ploug等，Biochemistry34(39)12524-12534，1995；Ploug等，Biochemistry 37(11)3612-3622，1998)和NMR干擾研究(Stephens等，Biochemistry317572-7579，1992)。
涉及藥劑與HBV聚合酶的“相互作用互補(bǔ)性程度的測(cè)定”時(shí)，應(yīng)當(dāng)理解為參照所關(guān)心任何特征的闡明，包括但不限于，HBV聚合酶和所關(guān)心藥劑之間相互作用的性質(zhì)和/或程度。如上所述，可以利用任何合適的技術(shù)。這樣的技術(shù)是本領(lǐng)域技術(shù)人員已知的。就主體相互作用的性質(zhì)而言，希望測(cè)定相互作用機(jī)理的類型，該機(jī)理發(fā)生在任何給定藥劑的特異性殘基和HBV聚合酶的那些殘基之間的(例如，肽結(jié)合或氫鍵、離子鍵，范德瓦爾斯力的形成，等)和/或它們的相對(duì)強(qiáng)度。還希望測(cè)定所關(guān)心藥劑和主體HBV聚合酶之間所發(fā)生的相互作用的程度。例如，通過(guò)分析主體藥劑和HBV聚合酶之間相互所用的實(shí)際位點(diǎn)，可以測(cè)定藥劑適合HBV聚合酶任何區(qū)域的性質(zhì)，以及結(jié)合相互作用的相對(duì)強(qiáng)度和穩(wěn)定性。這尤其涉及測(cè)定藥劑結(jié)合的性質(zhì)和位置。例如，當(dāng)希望抑制HBV聚合酶活性時(shí)，可以設(shè)計(jì)或鑒定結(jié)合核苷酸結(jié)合口袋的核苷類似物藥劑?；蛘?，可以鑒定與HBV相互作用的藥劑，使得阻斷或另外阻礙(例如，立體阻礙或化學(xué)和靜電阻礙)核苷酸或核酸模板結(jié)合HBV聚合酶分子。因此，涉及“相互作用”應(yīng)當(dāng)理解為包括涉及為了抑制HBV復(fù)制的目的，與一個(gè)或多個(gè)HBV結(jié)合區(qū)域相關(guān)的藥劑。在這點(diǎn)上，涉及抑制HBV聚合酶活性需要的相關(guān)形式可以不包括任何傳統(tǒng)理解的相互作用結(jié)合機(jī)理的形成，但可以包括非結(jié)合機(jī)理如藥劑相對(duì)于HBV聚合酶主體結(jié)合區(qū)域的接近定位，例如，對(duì)于核苷酸結(jié)合結(jié)合口袋，來(lái)影響位阻。當(dāng)相互作用采用阻礙的形式或其它斥(replusive)力的形成，盡管缺少任何傳統(tǒng)形式結(jié)合機(jī)理的形成，仍然將這理解為“相互作用”的形式。
應(yīng)當(dāng)理解為評(píng)價(jià)推斷藥劑之相互作用互補(bǔ)性的本發(fā)明之抗病毒藥物抗性HBV聚合酶(以物理形式或作為圖像所利用)，如在此所討論的，可以是天然生成形式的HBV聚合酶，或可以是其衍生物、同系物、類似物、突變體、片段或等價(jià)物。如詳細(xì)地，涉及聚合酶自身，其衍生物、同系物、類似物、突變體。片段或等價(jià)物也可以采用物理或非物理(如圖像)形式。
衍生物包括任何來(lái)源的片段、部分、局部、變體和模擬物，包括融合蛋白。部分或片段包括，例如，HBV聚合酶分子的活性片段。這尤其相關(guān)，例如，如果本領(lǐng)域技術(shù)人員對(duì)分析核苷酸結(jié)合區(qū)域有興趣。例如，并不是以任何方式限制本發(fā)明，認(rèn)為引入的核苷酸與存在于HBV聚合酶“手掌”亞結(jié)構(gòu)域的殘基相互反應(yīng)。一些情況下，僅測(cè)定HBV聚合酶分子包括這些結(jié)合區(qū)域的片段是有用的。因此，僅需要分離、合成、生產(chǎn)或描述一個(gè)或多個(gè)HBV結(jié)構(gòu)域或分離結(jié)構(gòu)域的部分。因此，應(yīng)當(dāng)理解本發(fā)明拓寬至使用HBV聚合酶分子的任何片段、部分或部分。衍生物可以源自氨基酸的插入、刪除或取代。氨基酸插入衍生物包括氨基和/或羧基端融合以及單個(gè)或多個(gè)氨基酸的序列內(nèi)插入。這尤其相關(guān)，當(dāng)希望將本發(fā)明的方法運(yùn)用至分析推斷藥劑和HBV聚合酶的突變體、變體或模擬物之間的相互作用時(shí)。插入氨基酸序列變體是其中將一個(gè)或多個(gè)氨基酸殘基引入預(yù)定位點(diǎn)蛋白質(zhì)中的那些，盡管用所得到產(chǎn)品的合適篩選隨機(jī)插入也是可能的。刪除變體通過(guò)從序列中除去一個(gè)或多個(gè)氨基酸來(lái)表征。取代氨基酸變體是其中序列中已經(jīng)除去至少一個(gè)殘基并在其位置插入不同殘基的那些。取代氨基酸變體的實(shí)例是保守氨基酸取代。保守氨基酸取代通常包括以下基團(tuán)中的取代甘氨酸和丙氨酸；纈氨酸、異亮氨酸和亮氨酸；天冬氨酸和谷氨酸；天冬酰胺和谷氨酰胺；絲氨酸和蘇氨酸；賴氨酸和精氨酸；以及苯丙氨酸和賴氨酸。除了氨基酸序列，包括與其它肽、多肽或蛋白質(zhì)的融合。
本發(fā)明HBV聚合酶的等價(jià)物應(yīng)當(dāng)理解為包括呈現(xiàn)任何一個(gè)或多個(gè)所述HBV聚合酶結(jié)構(gòu)特征的分子如化學(xué)等價(jià)物，并可以源自任何來(lái)源如化學(xué)合成、理論上推斷的或通過(guò)篩選方法如天然產(chǎn)物篩選鑒定的。
衍生物還包括具有融合于肽、多肽或其它蛋白質(zhì)或非蛋白質(zhì)分子的完整蛋白質(zhì)的特定區(qū)域或部分的片段。
涉及“同系物”是應(yīng)當(dāng)理解為涉及源自其它病毒的聚合酶或來(lái)自病毒的其它基本上相似的分子或相同分子的剪接變體。
在此涉及的類似物包括，但不限于，側(cè)鏈的修飾、非天然氨基酸的摻入和/或在肽、多肽或蛋白質(zhì)合成中的衍生物，和使用利用構(gòu)象構(gòu)建蛋白質(zhì)分子或其類似物的交聯(lián)物或其它方法。該研究和抗病毒抗性HBV聚合酶類似物的使用還可以用于涉及鑒定、研究和/或調(diào)節(jié)所述聚合酶突變體、變體或模擬物的活性。
本發(fā)明涉及的側(cè)鏈修飾的實(shí)例包括氨基的修飾如通過(guò)與醛反應(yīng)接著用NaBH4還原的還原性烷基化；用甲基亞氨逐乙酸的脒化；用乙酸酐的?；?；用氰酸鹽使氨基甲氨酰化；用2，4，6-三硝基苯磺酸(TNBS)的氨基三硝基苯化；用琥珀酸酐和四水鄰苯二甲酸酐進(jìn)行氨基的?；?；以及用吡哆醛-5-磷酸并接著用NaBH4還原進(jìn)行賴氨酸的吡哆化。
可以用如2，3-丁二酮、苯甲酰甲醛和乙二醛的試劑通過(guò)雜環(huán)縮合產(chǎn)物的形成來(lái)修飾精氨酸殘基的胍基。
可以通過(guò)碳化二亞胺激活，通過(guò)O-?；愲逍纬山又ㄟ^(guò)隨后的衍生，例如，衍生成相應(yīng)的酰胺來(lái)修飾羧基。
可以通過(guò)以下方法來(lái)修飾巰基，如用碘乙酸或碘乙酰胺的羧甲基化；過(guò)甲酸氧化成磺基丙氨酸；用其它硫醇化合物形成混合的二硫化物；與馬來(lái)酰亞胺、馬來(lái)酐或其它取代的馬來(lái)酰亞胺反應(yīng)；使用4-氯汞苯甲酸、4-氯汞苯基磺酸、苯基汞氯化物、2-氯汞-4-硝基酚和其它含汞的形成汞衍生物；用氰酸鹽在堿性pH下進(jìn)行甲氨?；?。
可以修飾色氨酸殘基，例如，用N-溴代琥珀酰亞胺氧化或用2-羥基-5-硝基苯基溴化物或磺苯基鹵化物進(jìn)行吲哚環(huán)的烷化。另一方面，可以改變酪氨酸，通過(guò)用四硝基甲烷硝化來(lái)形成3-硝基酪氨酸衍生物。
可以完成組氨酸殘基的咪唑環(huán)的修飾，通過(guò)用碘乙酸衍生物的烷化或用二乙基焦碳酸酯的N-碳乙氧基化。
在蛋白質(zhì)合成中摻入非天然氨基酸和衍生物的實(shí)例，包括但不限于，使用正亮氨酸、4-氨基丁酸、4-氨基-3-羥基-5-苯基戊酸、6-氨基己酸、叔丁基甘氨酸、正纈氨酸、苯基甘氨酸、鳥(niǎo)氨酸、肌氨酸、4-氨基-3-羥基-6-甲基庚酸、2-噻吩基丙氨酸和/或氨基酸的D-異構(gòu)體。在此涉及的非天然氨基酸列表顯示于表5中。
表5非常規(guī)氨基酸為密碼
例如，可以使用交聯(lián)劑來(lái)穩(wěn)定3D構(gòu)象，使用同型雙功能交聯(lián)劑如雙功能亞氨酯，其具有(CH2)n間隔基基團(tuán)，n＝1至n＝6，戊二醛、N-羥基琥珀酰亞胺酯，和雜雙功能藥劑，其通常含有氨基反應(yīng)性部分(如N-羥基琥珀酰亞胺)和另一基團(tuán)特異性反應(yīng)性部分。
HBV聚合酶三維結(jié)構(gòu)的闡明有助于鑒定和分析涉及HBV聚合酶和抗病毒藥物之間結(jié)合的區(qū)域?？共《舅幬锏膶?shí)例包括，特別是，核苷或核苷酸類似物如ADV、LMV、FCV、FTC、ETV、TDF、DAPD和DXG。例如，但不是限制本發(fā)明，任何一種作用的理論或模型，就其作為核苷酸結(jié)合口袋的部分或改變核苷酸結(jié)合口袋構(gòu)象的潛在功能而言，已經(jīng)分析了存在于HBV聚合酶上的單個(gè)殘基和殘基片段的定位?；谠摲治觯琀BV聚合酶殘基涉及測(cè)定結(jié)合口袋的構(gòu)象，或改變根據(jù)本發(fā)明已經(jīng)鑒定的核苷酸結(jié)合口袋的通路。這些殘基的突變具有潛能來(lái)改變，該核苷酸或核苷類似物可以結(jié)合HBV聚合酶的核苷酸結(jié)合口袋。這些殘基通過(guò)參照氨基酸殘基的編號(hào)識(shí)別或?qū)?yīng)于編號(hào)殘基的氨基酸殘基片段來(lái)限定，如詳述于SEQ ID NO1的或限定HBV聚合酶具有SEQ IDNO1至少70％相似性的氨基酸序列。通過(guò)單個(gè)編號(hào)和相鄰的如編號(hào)范圍的肽片段來(lái)鑒定單個(gè)殘基。
以下提出的一個(gè)或多個(gè)氨基酸或氨基酸的區(qū)域涉及核苷酸或核酸類似物的結(jié)合，選自氨基酸殘基28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257或4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266
rtA21，rtA38，rtY54，rtN76，rtL91，rtF122，rtY124，rtT128，rtQ130，rtT184，rtM204，rtS202，rtH248，rtY252，rtS21，rtN/S/T/I/V53，rtY54，rtS57，rtL91，rtS116，rtL122，rtF122，rtN124，rtY124 rtH126，rtY126，rtT128N，rtP130，rtD131，rtV134，rtY135，rtY141，rtL145，rtF151，rtL180，rtA181，rtS202，rtI204，rtK212，rtL217，rtS219，rtI235，rtN236，rtN238，sP120，sM125，sS126，sT127，sT118，sM133，sM133，sF134，sS143，sD144，sG145，sW172，sI195，sS207，sY225，間隔基L97，間隔基K115，間隔基H116，間隔基L128，間隔基S137，間隔基R139，間隔基F142，rtA97，rtH126，rtS135，rtM204，PreS1N114，PreS1 T115，PreS2 F22，PreS2 V39，PreS2 P52，sL89，sT118，sF161，sE164，sI195，sI208，PreS1 E86，PreS1 N91，PreS2 P41，sQ30，sP120，sL176，sV194，rtS21，rtL122，rtN124，rtH126，rtP130，rtD131，rtY135，rtN/S/T/I/V53，rtY126，rtS202，rtI204，rtI235，sM125，sT127，sT118，sM133，sF134，sI195，sS207，sY225，rtG172，rtG174，rtP177，rtL180，rtT184，sR160，sE164，sF170，sL175，sQ181，sC/W182，sW196，sW196，sW196，sM198，sW199，sS204，sY206，sS210，sS210，sL216，sY255，rtL77，rtL77，rtL80，rtL80，rtH90，rtS117，rt125，rt128，rtQ125，rtQ125，rtY126Q，rtL128，rtT128，rtL132，rtN134，rtS137，rtN139，rtN139，rtY141，rtV/G142，rtL147，rtK149，rtG153，rtR153，rtW153，rtW153，rtF166，rtI169，rtF178，rtI187，rtI187，rtV191，rtV191，rtN202，rtS202，rtS202，rtS213，rtV/G214，rtS219，rtS219，rtN/Q238，rtN/S/H238，rtN/S/H/T238，rtR242，rtR242，rtN248，rtI253，s118-207，s117-120，s168，sC69，sL109，sG112，sS17，sT118，sK122，sT123，sT126，sT131，sN131，sM133，sM133，sY/F134，sC139，sK141，sD144，sG145，rtT128，rtL82，rtT135，rtT150，rtV163，rtT184，rtA200，rtF202，rtS213，rtQ215，rtS219，rtA222，rtI224，rtL229，rtL235，rtN238，rtS78，rt116DEL122，rtI163，rtL180，rtE8，rtV23，rtD31，rtY53，rtV58，rtA/S21，rtV/I/N/S/T53，rtV/I/N/S/T53，rtS/T/N/H/A54，PreS2 L11，PreS2 R17，DEL PreS2 18-21，PreS2 T30，PreS2 N54，sT13，PreS2 Q1，PreS2 Q1，rtH90，rtL/F108，rtL157，rtA181，rtV207，rtP109，rtN/H/A/S/Q238，s181，sP214，sF83，sL173，sW199，sI126，sK160，sS174，sA84，sS210，sC69，sC76，si110，sY134或sW172.
本發(fā)明的另一方面提供了使用編程計(jì)算機(jī)來(lái)鑒定藥劑的計(jì)算機(jī)輔助方法，該藥劑潛在能夠結(jié)合HBV聚合酶的結(jié)構(gòu)域并任選地調(diào)節(jié)至少一種HBV聚合酶的功能活性，該方法包括預(yù)測(cè)對(duì)藥劑的抗病毒反應(yīng)，包括步驟
(a)將包括HBV聚合酶原子坐標(biāo)的數(shù)據(jù)輸入編程的計(jì)算機(jī)中，該聚合酶具有選自氨基酸殘基28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257或4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266區(qū)域內(nèi)的突變，諸如但不限于rtA21S，rtA38E，rtY54H，rtN76D，rtL91I，rtF122L，rtY124H，rtT128N，rtQ130P，rtT184G，rtM204V/I，rtS202I，rtH248N，rtY252L，rtS21A，rtN/S/T/I/V53D，rtY54H，rtS57P，rtL91I，rtS116P，rtL122F，rtF122L，rtN124H，rtY124H，rtH126R，rtY126Q，rtT128N，rtP130Q，rtD131N，rtV134D，rtY135C，rtY141Y/F，rtL145M，rtF151T/F，rtL180M，rtA181T，rtS202G，rtI204V，rtK212R，rtL217R，rtS219A，rtI235I/M，rtN236T，rtN238D，sP120T，sM125T，sS126T，sT127A，sT118R，sM133L/M，sM133T，sF134V，sS143S/T，sD144A，sG145A，sW172Stop，sI195M，sS207R，sY225Y/C，間隔基L97I，間隔基K115R，間隔基H116L，間隔基L128F，間隔基S137G，間隔基R139G，間隔基F142S，rtA97V，rtH126R，rtS135Y，rtM04I，PreS1 N114D，PreS1 T115S，PreS2 F22L，PreS2 V39A，PreS2 P52L，sL89V，sT118A，sF161L，sE164D，sI195M，sI208T，PreS1 E86Q，PreS1 N91K，PreS2 P41H，sQ30K，sP120T，sL176V，sV194F，rtS21A，rtL122F，rtN124H，rtH126R，rtP130Q，rtD131N，rtY135C，rtN/S/T/I/V53D，rtY126Q，rtS202G，rtI204V，rtI235I/M，sM125T，sT127A，sT118R，sM133T，sF134V，sI195M，sS207R，sY225Y/C，rtG172E，rtG174C，rtP177L，rtL180V，rtT184S，sR160N，sE164D，sF170L，sL175L/S，sQ181E/G/Q，sC/W182Y/STOP，sW196L，sW196S，sW196STOP，sM198I，sW199S，sS204T，sY206N，sS210K，sS210R，sL216STOP，sY255F，rtL77L/F，rtL77L/M/V，rtL80I，rtL80V，rtH90N/H，rtS117S/Y，rt125DELrt128，rtQ125K，rtQ125N，rtY126Q，rtL128L/M，rtT128A，rtL132L/M，rtN134G，rtS137T，rtN139H，rtN139K，rtY141Y/STOP，rtV/G142L，rtL147L/W，rtK149R，rtG153E，rtR153Q，rtW153S，rtW153Q，rtF166L，rtI169L，rtF178F/L，rtI187L，rtI187I/V，rtV191I，rtV191V/I，rtN202S，rtS202S/C，rtS202G，rtS213T，rtV/G214E，rtS219A，rtS219P，rtN/Q238H，rtN/S/H238N/K，rtN/S/H/T238/T/A/S/L，rtR242R/K，rtR242R/S，rtN248H，rtI253A，s118-207，s117-120DEL，sI68I/M，sC69F/L，sL109I/L，sG112R，sS17T，sT118R，sK122R，sT123P，sT126S，sT131N，sN131T，sM133K/M，sM133I，sY/F134S，sC139C/G，sK141E，sD144E，sG145R，rtT128T/I，rtL82M，rtT135C，rtT150A，rtV163I，rtT184S，rtA200V，rtF202V，rtS213T，rtQ215H，rtS219A，rtA222T，rtI224S，rtL229M，rtL235I，rtN238S，rtS78T，rt116DEL122，rtI163V，rtL180V，rtE8A，rtV23I，rtD31D/G，rtY53D，rtV58V/I，rtA/S21T，rtV/I/N/S/T53D，rtV/I/N/S/T53Y，rtS/T/N/H/A54Y/H，PreS2L11L/A，PreS2 R17I，DEL PreS2 18-21，PreS2 T30A，PreS2 N54H，sT13T/A，PreS2 Q1V，PreS2 Q1M，rtH90D，rtL/F108L，rtL157L/M，rtA181V，rtV207I，rtP109S，rtN/H/A/S/Q238K，s181M，sP214Q，sF83S，sL173F，sW199L，sI126T，sK160R，sS174N，sA84V，sS210N，sC69STOP/C，sC76Y，si110V/I，sY134N，sW172STOP/W，K32M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；N33D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；P34S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；H35I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；T37W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P59S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；K60M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；F61P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；A62R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；V63A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；D83C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/缺失；V84A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；S85T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；A86R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Y89V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；H90I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；I/L91K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/缺失；P177S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；F178P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；L179K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；L180K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；A181R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Q183E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；F183P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；
T184W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；Y203V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；M204F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；L235K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N236D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；T237W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P237S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；N238D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H238I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；A238R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；S239T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；Q238E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；K239M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；L247K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N248D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H248I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；F249P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；M250F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；G251H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/O/E/缺失；和V251A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；(b)使用計(jì)算機(jī)方法，產(chǎn)生與(a)中限定的原子坐標(biāo)具有立體化學(xué)互補(bǔ)性結(jié)構(gòu)的一套原子坐標(biāo)或其子集，由此產(chǎn)生標(biāo)準(zhǔn)數(shù)據(jù)集；(c)使用處理器，將標(biāo)準(zhǔn)數(shù)據(jù)集包括于化學(xué)結(jié)構(gòu)的計(jì)算機(jī)數(shù)據(jù)庫(kù)；(d)使用計(jì)算機(jī)方法，從數(shù)據(jù)庫(kù)中選擇與所述標(biāo)準(zhǔn)數(shù)據(jù)集的部分相似的化學(xué)結(jié)構(gòu)；和(e)輸出所選擇的與標(biāo)準(zhǔn)數(shù)據(jù)集的部分相似的化學(xué)結(jié)構(gòu)。
優(yōu)選地，該方法進(jìn)一步包括獲得具有步驟(d)和(e)中所選化學(xué)結(jié)構(gòu)的藥劑，并測(cè)試化合物調(diào)節(jié)至少一種HBV聚合酶的功能活性的能力。
本發(fā)明的再一方面提供了計(jì)算機(jī)或其軟件部分，用于產(chǎn)生分子或分子復(fù)合物的三維圖像，其包括分子或分子復(fù)合物的同系物的三維圖像，其中同系物包括氨基酸主鏈原子的標(biāo)準(zhǔn)差不大于1.5_的結(jié)構(gòu)域，其中計(jì)算機(jī)包括(a)機(jī)器可讀的數(shù)據(jù)存儲(chǔ)介質(zhì)，包括用機(jī)器可讀數(shù)據(jù)編碼的數(shù)據(jù)存儲(chǔ)材料，其中數(shù)據(jù)包括HBV聚合酶的坐標(biāo)，聚合酶具有選自氨基酸殘基28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257，或4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266區(qū)域內(nèi)的突變，諸如但不限于 rtA21S，rtA38E，rtY54H，rtN76D，rtL91I，rtF122L，rtY124H，rtT128N，rtQ130P，rtT184G，rtM204V/I，rtS202I，rtH248N，rtY252L，rtS21A，rtN/S/T/I/V53D，rtY54H，rtS57P，rtL91I，stS116P，rtL122F，rtF122L，rtN124H，rtY124H，rtH126R，rtY126Q，rtT128N，rtP130Q，rtD131N，rtV134D，rtY135C，rtY141Y/F，rtL145M，rtF151T/F，rtL180M，rtA181T，rtS202G，rtI204V，rtK212R，rtL217R，rtS219A，rtI235I/M，rtN236T，rtN238D，sP120T，sM125T，sS126T，sT127A，sT118R，sM133L/M，sM133T，sF134V，sS143S/T，sD144A，sG145A，sW172Stop，sI195M，sS207R，sY225Y/C，間隔基L97I，間隔基K115R，間隔基H116L，間隔基L128F，間隔基S137G，間隔基R139G，間隔基F142S，rtA97V，rtH126R，rtS135Y，rtM204I，PreS1 N114D，PreS1 T115S，PreS2 F22L，PreS2 V39A，PreS2 P52L，sL89V，sT118A，sF161L，sE164D，sI195M，sI208T，PreS1 E86Q，PreS1 N91K，PreS2 P41H，sQ30K，sP120T，sL176V，sV194F，rtS21A，rtL122F，rtN124H，rtH126R，rtP130Q，rtD131N，rtY135C，rtN/S/T/I/V53D，rtY126Q，rtS202G，rtI204V，rtI235I/M，sM125T，sT127A，sT118R，sM133T，sF134V，sI195M，sS207K，sY225Y/C，rtG172E，rtG174C，rtP177L，rtL180V，rtT184S，sR160N，sE164D，sF170L，sL175L/S，sQ181E/G/Q，sC/W182Y/STOP，sW196L，sW196S，sW196STOP，sM198I，sW199S，sS204T，sY206N，sS210K，sS210R，sL216STOP，sY255F，rtL77L/F，rtL77L/M/V，rtL80I，rtL80V，rtH90N/H，rtS117S/Y，rt125DELrt128，rtQ125K，rtQ125N，rtY126Q，rtL128L/M，rtT128A，rtL132L/M，rtN134G，rtS137T，rtN139H，rtN139K，rtY141Y/STOP，rtV/G142L，rtL147L/W，rtK149R，rtG153E，rtR153Q，rtW153S，rtW153Q，rtF166L，rtI169L，rtF178F/L，rtI187L，rtI187I/V，rtV191I，rtV191V/I，rtN202S，rtS202S/C，rtS202G，rtS213T，rtV/G214E，rtS219A，rtS219P，rtN/Q238H，rtN/S/H238N/K，rtN/S/H/T238/T/A/S/L，rtR242R/K，rtR242R/S，rtN248H，rtI253A，s118-207，s117-120DEL，sI68I/M，sC69F/L，sL109I/L，sG112R，sS17T，sT118R，sK122R，sT123P，sT126S，sT131N，sN131T，sM133K/M，sM133I，sY/F134S，sC139C/G，sK141E，sD144E，sG145R，rtT128T/I，rtL82M，rtT135C，rtT150A，rtV163I，rtT184S，rtA200V，rtF202V，rtS213T，rtQ215H，rtS219A，rtA222T，rtI224S，rtL229M，rtL235I，rtN238S，rtS78T，rt116DEL122，rtI163V，rtL180V，rtE8A，rtV23I，rtD31D/G，rtY53D，rtV58V/I，rtA/S21T，rtV/I/N/S/T53D，rtV/I/N/S/T53Y，rtS/T/N/H/A54Y/H，PreS2L11L/A，PreS2 R17I，DEL PreS2 18-21，PreS2 T30A，PreS2 N54H，sT13T/A，PreS2 Q1V，PreS2 Q1M，rtH90D，rtL/F108L，rtL157L/M，rtA181V，rtV207I，rtP109S，rtN/H/A/S/Q238K，s181M，sP214Q，sF83S，sL173F，sW199L，sI126T，sK160R，sS174N，sA84V，sS210N，sC69STOP/C，sC76Y，si110V/I，sY134N，sW172STOP/W，K32M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；N33D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；P34S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；H35I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；T37W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P59S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；K60M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；F61P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；A62R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；V63A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；D83C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/缺失；V84A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；S85T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；A86R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Y89V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；H90I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；I/L91K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/缺失；
P177S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；F178P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；L179K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；L180K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；A181R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Q183E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；F183P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；T184W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；Y203V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；M204F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；L235K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N236D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；T237W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P237S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；N238D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H238I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；A238R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；S239T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；Q238E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；K239M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；L247K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N248D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H248I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；F249P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；M250F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；G251H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/缺失；和V251A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；(b)存儲(chǔ)處理機(jī)器可讀數(shù)據(jù)的指令的工作存儲(chǔ)器；(c)連接于工作存儲(chǔ)器和機(jī)器可讀數(shù)據(jù)存儲(chǔ)介質(zhì)的中央處理單元，用于將機(jī)器可讀數(shù)據(jù)處理成三維圖像；和(d)連接于中央處理單元的顯示器，用于顯示三維結(jié)構(gòu)圖像。
一實(shí)施方案中，三維圖像是表6中所列的一套結(jié)構(gòu)坐標(biāo)限定的HBV聚合酶或其中三維圖像是分子或分子復(fù)合物的同系物，同系物具有不大于1.5_的氨基酸主鏈原子的標(biāo)準(zhǔn)差。
本發(fā)明的再一方面提供了計(jì)算機(jī)或其軟件部分，用于測(cè)定對(duì)應(yīng)于包括HBV聚合酶的分子或分子復(fù)合物三維結(jié)構(gòu)的至少部分結(jié)構(gòu)坐標(biāo)，其中計(jì)算機(jī)包括(a)機(jī)器可讀數(shù)據(jù)存儲(chǔ)介質(zhì)，包括機(jī)器可讀數(shù)據(jù)編碼的數(shù)據(jù)存儲(chǔ)材料，其中數(shù)據(jù)包括至少部分的HBV聚合酶結(jié)構(gòu)坐標(biāo)，聚合酶具有選自氨基酸殘基28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257，或4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266區(qū)域內(nèi)的突變，諸如但不限于rtA21S，rtA38E，rtY54H，rtN76D，rtL91I，rtF122L，rtY124H，rtT128N，rtQ130P，rtT184G，rtM204V/I，rtS202I，rtH248N，rtY252L，rtS21A，rtN/S/T/I/V53D，rtY54H，rtS57P，rtL91I，rtS116P，rtL122F，rtF122L，rtN124H，rtY124H，rtH126R，rtY126Q，rtT128N，rtP130Q，rtD131N，rtV134D，rtY135C，rtY141Y/F，rtL145M，rtF151T/F，rtL180M，rtA181T，rtS202G，rtI204V，rtK212R，rtL217R，rtS219A，rtI235I/M，rtN236T，rtN238D，sP120T，sM125T，sS126T，sT127A，sT118R，sM133L/M，sM133T，sF134V，sS 143S/T，sD144A，sG145A，sW172Stop，sI195M，sS207R，sY225Y/C，間隔基L97I，間隔基K115R，間隔基H116L，間隔基L128F，間隔基S137G，間隔基R139G，間隔基F142S，rtA97V，rtH126R，rtS135Y，rtM204I，PreS1 N114D，PreS1 T115S，PreS2 F22L，PreS2V39A，PreS2 P52L，sL89V，sT118A，sF161L，sE164D，sI195M，sI208T，PreS1E86Q，PreS1 N91K，PreS2 P41H，sQ30K，sP120T，sL176V，sV194F，rtS21A，rtL122F，rtN124H，rtH126R，rtP130Q，rtD131N，rtY135C，rtN/S/T/I/V53D，rtY126Q，rtS202G，rtI204V，rtI235I/M，sM125T，sT127A，sT118R，sM133T，sF134V，sI195M，sS207R，sY225Y/C，rtG172E，rtG174C，rtP177L，rtL180V，rtT184S，sR160N，sE164D，sF170L，sL175L/S，sQ181E/G/Q，sC/W182Y/STOP，sW196L，sW196S，sW196STOP，sM198I，sW199S，sS204T，sY206N，sS210K，sS210R，sL216STOP，sY255F，rtL77L/F，rtL77L/M/V，rtL80I，rtL80V，rtH90N/H，rtS117S/Y，rt125DELrt128，rtQ125K，rtQ125N，rtY126Q，rtL128L/M，rtT128A，rtL132L/M，rtN134G，rtS137T，rtN139H，rtN139K，rtY141Y/STOP，rtV/G142L，rtL147L/W，rtK149R，rtG153E，rtR153Q，rtW153S，rtW153Q，rtF166L，rtI169L，rtF178F/L，rtI187L，rtI187I/V，rtV191I，rtV191V/I，rtN202S，rtS202S/C，rtS202G，rtS213T，rtV/G214E，rtS219A，rtS219P，rtN/Q238H，rtN/S/H238N/K，rtN/S/H/T238/T/A/S/L，rtR242R/K，rtR242R/S，rtN248H，rtI253A，s118-207，s117-120DEL，sI68I/M，sC69F/L，sL109L/L，sG112R，sS17T，sT118R，sK122R，sT123P，sT126S，sT131N，sN131T，sM133K/M，sM133I，sY/F134S，sC139C/G，sK141E，sD144E，sG145R，rtT128T/I，rtL82M，rtT135C，rtT150A，rtV163I，rtT184S，rtA200V，rtF202V，rtS213T，rtQ215H，rtS219A，rtA222T，rtI224S，rtL229M，rtL235I，rtN238S，rtS78T，rt116DEL122，rtI163V，rtL180V，rtE8A，rtV23I，rtD31D/G，rtY53D，rtV58V/I，rtA/S21T，rtV/I/N/S/T53D，rtV/I/N/S/T53Y，rtS/T/N/H/A54Y/H，PreS2 L11L/A，PreS2 R17I，DEL PreS2 18-21，PreS2 T30A，PreS2 N54H，sT13T/A，PreS2 Q1V，PreS2 Q1M，rtH90D，rtL/F108L，rtL 157L/M，rtA181V，rtV207I，rtP109S，rtN/H/A/S/Q238K，s181M，sP214Q，sF83S，sL173F，sW199L，sI126T，sK160R，sS174N，sA84V，sS210N，sC69STOP/C，sC76Y，si110V/I，sY134N，sW172STOP/W，K32M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；N33D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；P34S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；H35I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；T37W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P59S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；K60M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；F61P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；A62R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；V63A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；D83C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/缺失；V84A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；S85T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；A86R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Y89V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；
H90I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；I/L91K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/缺失；P177S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；F178P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；L179K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；L180K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；A181R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Q183E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；F183P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；T184W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；Y203V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；M204F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；L235K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N236D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；T237W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P237S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；N238D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H238I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；A238R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；S239T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；Q238E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；K239M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；L247K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N248D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H248I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；F249P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；M250F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；G251H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/缺失；和V251A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；
(b)機(jī)器可讀數(shù)據(jù)存儲(chǔ)介質(zhì)，包括機(jī)器可讀數(shù)據(jù)編碼的數(shù)據(jù)存儲(chǔ)材料，其中數(shù)據(jù)包括分子或分子復(fù)合物的原子坐標(biāo)；(c)工作存儲(chǔ)器，用于存儲(chǔ)處理(a)和(b)的機(jī)器可讀數(shù)據(jù)的指令；(d)連接于工作存儲(chǔ)器以及(a)和(b)的機(jī)器可讀數(shù)據(jù)存儲(chǔ)介質(zhì)的中央處理單元，用于進(jìn)行(a)的機(jī)器可讀數(shù)據(jù)轉(zhuǎn)換和用于將(b)的機(jī)器可讀數(shù)據(jù)處理成結(jié)構(gòu)坐標(biāo)；和(e)連接于中央處理單元的顯示器，用于顯示分子或分子復(fù)合物的結(jié)構(gòu)坐標(biāo)。
更特別地，計(jì)算機(jī)產(chǎn)物是基于參與核苷或核苷酸類似物結(jié)合的氨基酸殘基。因此，本發(fā)明提供了使用編程的計(jì)算機(jī)來(lái)鑒定藥劑的計(jì)算機(jī)輔助方法，該藥劑潛在地能夠結(jié)合HBV聚合酶的結(jié)構(gòu)域，且任選地調(diào)節(jié)至少一種HBV聚合酶的功能活性，包括預(yù)測(cè)對(duì)藥劑的抗病毒反應(yīng)，該方法包括步驟(a)將數(shù)據(jù)輸入編程的計(jì)算機(jī)，數(shù)據(jù)包括HBV聚合酶的原子坐標(biāo)或其位于28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257，和/或位于位置編號(hào)4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266片段的原子坐標(biāo)；(b)使用計(jì)算機(jī)方法，產(chǎn)生與(a)中限定的原子坐標(biāo)具有立體化學(xué)互補(bǔ)性結(jié)構(gòu)的一套原子坐標(biāo)或其子集，由此產(chǎn)生標(biāo)準(zhǔn)數(shù)據(jù)集；(c)使用處理器，將標(biāo)準(zhǔn)數(shù)據(jù)集包括于化學(xué)結(jié)構(gòu)的計(jì)算機(jī)數(shù)據(jù)庫(kù)；(d)使用計(jì)算機(jī)方法，從數(shù)據(jù)庫(kù)中選擇與所述標(biāo)準(zhǔn)數(shù)據(jù)集的部分相似的化學(xué)結(jié)構(gòu)；和(e)輸出所選擇的與標(biāo)準(zhǔn)數(shù)據(jù)集的部分相似的化學(xué)結(jié)構(gòu)。
根據(jù)本發(fā)明已經(jīng)特地研究了AVD和HBV聚合酶的結(jié)合。該相互作用圖示于圖6中?；谠摲治?，認(rèn)為涉及ADV結(jié)合的HBV聚合酶分子結(jié)合區(qū)域和特定殘基已經(jīng)得到鑒定。已經(jīng)鑒定了在特定氨基酸殘基具有替換的HBV聚合酶(當(dāng)和天然HBV聚合酶相比較時(shí))，其呈現(xiàn)了對(duì)ADV的抗性。涉及ADV與HBV聚合酶結(jié)合的在SEQ ID NO1提供的抗病毒藥物抗性HBV聚合酶序列中反映的特定氨基酸替換已經(jīng)得到了鑒定。參照天然HBV聚合酶這些替換詳述為rtN236T、rtA181T、rtA181V、rtV84N和rtH90D。
然而，為了在此限定方法的目的，達(dá)到使用任何其它HBV聚合酶的程度，這些區(qū)域定位的確切殘基標(biāo)號(hào)可以改變。應(yīng)當(dāng)理解本發(fā)明包括存在于除了SEQ ID NO1識(shí)別以外的HBV聚合酶分子形式上的等價(jià)區(qū)域和殘基。尤其是，對(duì)ADV、LMV、FCV、FTC、ETV、TDF、DAPD和DXG抗性的HBV聚合酶也包括于本發(fā)明中。通過(guò)參照最佳比對(duì)后與SEQID NO1具有至少約70％相似性的氨基酸序列來(lái)包括這樣的聚合酶。
這些潛在結(jié)合區(qū)域的測(cè)定可以通過(guò)闡明HBV聚合酶的三維結(jié)構(gòu)來(lái)獲得，該三維結(jié)構(gòu)有助于鑒定和/或合理改變并設(shè)計(jì)藥劑，根據(jù)本發(fā)明該藥劑可以用于結(jié)合抗病毒藥物抗性HBV聚合酶的核苷酸結(jié)合口袋。
因此，本發(fā)明的另一實(shí)施方案提供了鑒定能夠與抗病毒藥物抗性的HBV聚合酶相互作用的藥劑的方法，所述方法包括使抗病毒藥物抗性的HBV聚合酶或其衍生物、同系物、類似物、片段或等價(jià)物與藥劑接觸，該分子包括SEQ ID NO1所列的氨基酸序列或最佳比對(duì)后與SEQID NO1具有至少70％相似性的氨基酸序列，并測(cè)定所述藥劑與所述HBV聚合酶相互作用互補(bǔ)性的程度，其中所述藥劑結(jié)合所述HBV聚合酶的核苷酸結(jié)合口袋。
該藥劑可以調(diào)節(jié)至少一種與HBV聚合酶相關(guān)的功能活性?？商鎿Q的或另外的，僅相互作用就足以使藥劑作為治療劑。
術(shù)語(yǔ)“調(diào)節(jié)”應(yīng)當(dāng)理解為指的是至少一種與HBV聚合酶相關(guān)功能活性的上調(diào)或下調(diào)。HBV聚合酶相關(guān)功能活性的下調(diào)，例如，抑制HBV的復(fù)制，特別理想的是在治療疾病中如肝炎。因此，本發(fā)明給對(duì)ADV或另一種抗病毒藥劑如核苷或核苷酸類似物沒(méi)反應(yīng)的肝炎提供了潛在的治療或預(yù)防。
因此，本發(fā)明涉及鑒定藥劑的方法，該藥劑能夠與抗病毒藥物抗性HBV聚合酶和/或野生型HBV聚合酶相互作用并任選地下調(diào)至少一種與所述HBV聚合酶相關(guān)的功能活性，其中所述抗病毒抗性HBV聚合酶和/或野生型HBV聚合酶具有至少一種以下特征(i)和天然HBV聚合酶相比，顯示對(duì)核苷類似物(如ADV、LMV、FCV、FTC、ETV、TDF、DAPD和DXG)提高的抗性或降低的敏感度；(ii)包括選自氨基酸殘基28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257或4-10、24-27、46-58、67-68、69-70、71-72、94-120、165-166、185-197、214-227、242-244和258-266片段內(nèi)的突變，如但不限于 rtA21S，rtA38E，rtY54H，rtN76D，rtL91I，rtF122L，rtY124H，rtT128N，rtQ130P，rtT184G，rtM204V/I，rtS202I，rtH248N，rtY252L，rtS21A，rtN/S/T/I/V53D，rtY54H，rtS57P，rtL91I，rtS116P，rtL122F，rtF122L，rtN124H，rtY124H，rtH126R，rtY126Q，rtT128N，rtP130Q，rtD131N，rtV134D，rtY135C，rtY141Y/F，rtL145M，rtF151T/F，rtL180M，rtA181T，rtS202G，rtI204V，rtK212R，rtL217R，rtS219A，rtI235I/M，rtN236T，rtN238D，sP120T，sM125T，sS126T，sT127A，sT118R，sM133L/M，sM133T，sF134V，sS143S/T，sD144A，sG145A，sW172Stop，sI195M，sS207R，sY225Y/C，間隔基L97I，間隔基K115R，間隔基H116L，間隔基L128F，間隔基S137G，間隔基R139G，間隔基F142S，rtA97V，rtH126R，rtS135Y，rtM204I，PreS1 N114D，PreS1 T115S，PreS2 F22L，PreS2 V39A，PreS2 P52L，sL89V，sT118A，sF161L，sE164D，sI195M，sI208T，PreS1 E86Q，PreS1 N91K，PreS2 P41H，sQ30K，sP120T，sL176V，sV194F，rtS21A，rtL122F，rtN124H，rtH126R，rtP130Q，rtD131N，rtY135C，rtN/S/T/I/V53D，rtY126Q，rtS202G，rtI204V，rtI235I/M，sM125T，sT127A，sT118R，sM133T，sF134V，sI195M，sS207R，sY225Y/C，rtG172E，rtG174C，rtP177L，rtL180V，rtT184S，sR160N，sE164D，sF170L，sL175L/S，sQ181E/G/Q，sC/W182Y/STOP，sW196L，sW196S，sW196STOP，sM198I，sW199S，sS204T，sY206N，sS210K，sS210R，sL216STOP，sY255F，rtL77L/F，rtL77L/M/V，rtL80I，rtL80V，rtH90N/H，rtS117S/Y，rt125DELrt128，rtQ125K，rtQ125N，rtY126Q，rtL128L/M，rtT128A，rtL132L/M，rtN134G，rtS137T，rtN139H，rtN139K，rtY141Y/STOP，rtV/G142L，rtL147L/W，rtK49R，rtG153E，rtR153Q，rtW153S，rtW153Q，rtF166L，rtI169L，rtF178F/L，rtI187L，rtI187I/V，rtV191I，rtV191V/I，rtN202S，rtS202S/C，rtS202G，rtS213T，rtV/G214E，rtS219A，rtS219P，rtN/Q238H，rtN/S/H238N/K，rtN/S/H/T238/T/A/S/L，rtR242R/K，rtR242R/S，rtN248H，rtI253A，s118-207，s117-120DEL，sI68I/M，sC69F/L，sL109I/L，sG112R，sS17T，sT118R，sK122R，sT123P，sT126S，sT131N，sN131T，sM133K/M，sM133I，sY/F134S，sC139C/G，sK141E，sD144E，sG145R，rtT128T/I，rtL82M，rtT135C，rtT150A，rtV163I，rtT184S，rtA200V，rtF202V，rtS213T，rtQ215H，rtS219A，rtA222T，rtI224S，rtL229M，rtL235I，rtN238S，rtS78T，rt116DEL122，rtI163V，rtL180V，rtE8A，rtV23I，rtD31D/G，rtY53D，rtV58V/I，rtA/S21T，rtV/I/N/S/T53D，rtV/I/N/S/T53Y，rtS/T/N/H/A54Y/H，PreS2L11L/A，PreS2 R17I，DEL PreS2 18-21，PreS2 T30A，PreS2 N54H，sT13T/A，PreS2 Q1V，PreS2 Q1M，rtH90D，rtL/F108L，rtL157L/M，rtA181V，rtV207I，rtP109S，rtN/H/A/S/Q238K，s181M，sP214Q，sF83S，sL173F，sW199L，sI126T，sK160R，sS174N，sA84V，sS210N，sC69STOP/C，sC76Y，si110V/I，sY134N，sW172STOP/W，K32M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；N33D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；P34S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；H35I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；T37W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P59S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；K60M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；F61P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；A62R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；V63A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；D83C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/缺失；V84A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；S85T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；A86R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Y89V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；
H90I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；I/L91K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/缺失；P177S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；F178P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；L179K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；L180K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；A181R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Q183E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；F183P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；T184W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；Y203V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；M204F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；L235K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N236D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；T237W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P237S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；N238D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H238I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；A238R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；S239T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；Q238E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；K239M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；L247K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N248D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H248I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；F249P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；M250F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；G251H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/缺失；和V251A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；和/或
(iii)包括SEQ ID NO1中所述的氨基酸序列或限定HBV聚合酶且在與SEQ ID NO1最佳比對(duì)后具有至少70％相似性序列的氨基酸序列；所述方法包括使所述抗病毒抗性HBV聚合酶分子或衍生物、同系物、類似物、片段、突變體或等價(jià)物接觸藥劑，并測(cè)定所述藥劑與所述抗病毒藥物抗性HBV聚合酶相互作用的互補(bǔ)性程度。
優(yōu)選地，HBV聚合酶的功能活性涉及HBV的復(fù)制。
更優(yōu)選地，在對(duì)ADV抗性或具有降低敏感度的HBV聚合酶的范圍內(nèi)，HBV聚合酶具有基本上與表6中所列相同的原子坐標(biāo)。
或者，藥劑與HBV聚合酶相互作用但不抑制HBV聚合酶。這樣的藥劑具有作為診斷劑的可能，如能夠區(qū)別不同菌株的HBV聚合酶。
應(yīng)當(dāng)理解與HBV聚合酶相關(guān)的“至少一種功能活性”的調(diào)節(jié)指的是與HBV復(fù)制相關(guān)功能活性的調(diào)節(jié)?！跋嚓P(guān)”意思是通過(guò)HBV聚合酶分子激活或鈍化的水平來(lái)直接或間接調(diào)節(jié)主體的功能活性。直接相關(guān)的功能活性包括但不限于，通過(guò)來(lái)自模板核酸的新核酸鏈重新合成的HBV染色體復(fù)制。
涉及“藥劑”時(shí)應(yīng)當(dāng)理解為實(shí)現(xiàn)本發(fā)明目的的任何蛋白質(zhì)或非蛋白質(zhì)分子，即調(diào)節(jié)至少一種與HBV聚合酶分子相關(guān)的功能活性。
蛋白質(zhì)分子可以源自天然或重組來(lái)源，包括融合蛋白或以下的，例如，天然產(chǎn)品篩選。非蛋白質(zhì)分子可以是例如合成分子，如化學(xué)合成的一種，或可以源自天然來(lái)源，如通過(guò)天然產(chǎn)物篩選獲得的。本發(fā)明包括能夠作為HBV聚合酶激動(dòng)劑或拮抗劑的核苷酸堿基化學(xué)類似物或小分子?；瘜W(xué)激動(dòng)劑不必需是源自HBV聚合酶分子配體，但具有特定的構(gòu)象相似性。
或者，可以特異設(shè)計(jì)化學(xué)激動(dòng)劑來(lái)模擬特定物化特征。拮抗劑可以是能夠阻斷、抑制或另外預(yù)防HBV聚合酶進(jìn)行其正常生物功能的任何化合物。拮抗劑和激動(dòng)劑特別包括單克隆抗體、小分子、肽或藥物。
不以任何方式限制本發(fā)明的應(yīng)用，本發(fā)明的方法有助于能夠與抗病毒藥物抗性HBV聚合酶分子相互作用的藥劑的鑒定、分析、設(shè)計(jì)和/或改進(jìn)。在這點(diǎn)上，這樣的藥劑可以通過(guò)以下來(lái)鑒定(i)隨機(jī)篩選(例如，利用常規(guī)的高通量篩選技術(shù))來(lái)鑒定呈現(xiàn)了一些關(guān)于HBV聚合酶功能活性調(diào)節(jié)能力的藥劑，并利用本發(fā)明的方法分析藥劑信號(hào)傳導(dǎo)能力的精確性質(zhì)和大小。在這點(diǎn)上，可以用藥劑浸透現(xiàn)有晶體或進(jìn)行共結(jié)晶。然后進(jìn)行局部化合物的模型化和合成修飾與HBV聚合酶誘變的組合。在篩選可以調(diào)節(jié)活性的藥劑中，可以使用噬菌體展示的標(biāo)準(zhǔn)方法以及組合化學(xué)(Goodson等，Proc.Natl.Acad.Sci.USA 91(15)7129-7133，1994；Terrett，DrugDiscov.Today 5(5)211-212，2000)。該相互作用的研究還可以進(jìn)一步利用如之前詳述的Biacore分析和NMR干擾研究的技術(shù)。就蛋白質(zhì)或非蛋白質(zhì)分子對(duì)于它們促效或拮抗功能能力的隨機(jī)篩選而言，這樣的藥劑通常稱為“前導(dǎo)”藥劑。此外，例如，通過(guò)改變前導(dǎo)藥劑來(lái)最大化與復(fù)合物結(jié)構(gòu)揭示的βc接近殘基的相互作用，從而可以提高結(jié)合親合性和特異性。這樣的分析有助于選擇最適于給定目的的藥劑。在這點(diǎn)上，選擇步驟不僅基于體外數(shù)據(jù)而且還基于藥劑HBV聚合酶分子的相互作用位點(diǎn)的技術(shù)分析，就其對(duì)于給定目的的頻率、穩(wěn)定性和適應(yīng)性而言。例如，根據(jù)本發(fā)明方法進(jìn)行的分析可以揭示對(duì)于隨機(jī)鑒定的藥劑，似乎是可接受的體外活性實(shí)際上是通過(guò)高度不穩(wěn)定相互作用誘導(dǎo)的，由于接近位置的藥劑HBV聚合酶分子位點(diǎn)的存在，該位點(diǎn)呈現(xiàn)顯著的斥力，因此使藥劑和HBV聚合酶分子之間的全部相互作用不穩(wěn)定。然后這將有助于選擇另一種具有希望的前導(dǎo)化合物，呈現(xiàn)相同程度的體外活性，但在進(jìn)一步分析時(shí)該藥劑沒(méi)有涉及這樣不穩(wěn)定斥力的存在。
在此限定的調(diào)節(jié)藥劑的篩選可以通過(guò)任一種本領(lǐng)域技術(shù)人員公知的且是例如為了鑒定前導(dǎo)化合物的目的常規(guī)用于隨機(jī)篩選蛋白質(zhì)或非蛋白質(zhì)分子的合適方法來(lái)獲得。例如，這樣的技術(shù)包括使感染的細(xì)胞接觸表達(dá)抗病毒抗性HBV的HBV并篩選HBV聚合酶功能活性的調(diào)節(jié)或包括調(diào)節(jié)病毒復(fù)制的HBV聚合酶誘導(dǎo)的下游功能活性?？梢岳眉夹g(shù)如蛋白質(zhì)印跡、電泳移動(dòng)率變動(dòng)分析和/或病毒在細(xì)胞培養(yǎng)物或動(dòng)物模型中的滴定度來(lái)獲得這樣調(diào)節(jié)的檢測(cè)。檢測(cè)技術(shù)的選擇將完全取決于作為檢測(cè)主體的HBV聚合酶特征的性質(zhì)。
應(yīng)當(dāng)理解HBV聚合酶分子或其功能等價(jià)物或衍生物可以在病毒感染不存在下在作為測(cè)試主體的細(xì)胞中轉(zhuǎn)基因表達(dá)，或可以是所述細(xì)胞感染HBV的結(jié)果。此外，基因可以組成型表達(dá)或?yàn)榱藢?shí)現(xiàn)表達(dá)需要刺激。此外，HBV聚合酶可以包括完整的HBV聚合酶分子基因或可以僅包括部分基因，如編碼一些HBV聚合酶結(jié)構(gòu)域的部分。
這些方法提供了進(jìn)行推斷調(diào)節(jié)藥劑高通量篩選的機(jī)理，藥劑如蛋白質(zhì)或非蛋白質(zhì)藥劑，包括合成的、重組的、化學(xué)的和天然文庫(kù)的。
(ii)為了最大化所需的相互作用(例如，對(duì)特異性的結(jié)合親合性)和最小化不理想的相互作用(如斥力或其它不穩(wěn)定的相互作用)可以用抗病毒抗性HBV聚合酶分子來(lái)修飾候選或前導(dǎo)藥劑(例如，根據(jù)關(guān)于點(diǎn)(i)所述方法鑒定的藥劑)。只有根據(jù)抗病毒抗性HBV聚合酶三維結(jié)構(gòu)的詳細(xì)知識(shí)和因此鑒定功能重要性片段的能力才可能進(jìn)行這樣的修飾，因此有助于藥劑的結(jié)構(gòu)修飾來(lái)最大化促效或拮抗作用。這樣的方法尤其適于合理的藥物設(shè)計(jì)。根據(jù)在此所述的目的候選或前導(dǎo)藥劑的修飾方法是本領(lǐng)域技術(shù)人員公知的。例如，在這點(diǎn)上可以利用分子置換程序(Navaza，Acta Cryst.A50157-163，1994)。為了消除或提高信號(hào)活性，本發(fā)明的方法還有助于已知信號(hào)誘導(dǎo)劑的誘變。
(iii)除了分析適應(yīng)和/或結(jié)構(gòu)修飾現(xiàn)有的分子，基于呈現(xiàn)所需HBV聚合酶分子相互作用結(jié)構(gòu)特征的理論模型，本發(fā)明的方法還有助于藥劑如激動(dòng)劑或拮抗劑的合理設(shè)計(jì)和合成，接著合成并測(cè)試該主體藥劑。
應(yīng)當(dāng)理解在鑒定特定藥劑中可以利用任何一種或多種上述(i)至(iii)的應(yīng)用。
如之前所詳述的，因?yàn)榭梢杂糜阼b定、分析、設(shè)計(jì)和/或改進(jìn)僅與HBV聚合酶分子結(jié)構(gòu)的一部分反應(yīng)的藥劑，涉及HBV聚合酶時(shí)包括其部分或片段。因此，應(yīng)當(dāng)理解本發(fā)明的方法特別拓寬為所預(yù)測(cè)的對(duì)HBV聚合酶生物活性或HBV聚合酶抗病毒藥劑抗性重要的合成肽到部分結(jié)構(gòu)的設(shè)計(jì)。
在這點(diǎn)上和在特別優(yōu)選的實(shí)施方案中，本發(fā)明的方法運(yùn)用于鑒定、分析、設(shè)計(jì)和/或改進(jìn)結(jié)合抗病毒抗性HBV聚合酶分子核苷酸結(jié)合口袋的藥劑，如核苷類似物。
在相關(guān)方面中，應(yīng)當(dāng)理解本發(fā)明包括利用在此所述方法所鑒定的藥劑。
因此，本發(fā)明涉及能夠與抗病毒抗性HBV聚合酶分子或野生型HBV聚合酶相互作用并任選地調(diào)節(jié)至少一種與所述聚合酶相關(guān)的功能活性的藥劑，其中所述抗病毒抗性HBV聚合酶和/或野生型HBV聚合酶具有至少一個(gè)以下特征(i)和天然HBV聚合酶相比較，對(duì)核苷類似物如ADV、LMV、FCV、FTC、ETV、DAPD和DXG顯示提高的抗性或降低的敏感度；(ii)包括選自氨基酸殘基28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257，或4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266片段中的突變，如但不限于rtA21S，rtA38E，rtY54H，rtN76D，rtL91I，rtF122L，rtY124H，rtT128N，rtQ130P，rtT184G，rtM204V/I，rtS202I，rtH248N，rtY252L，rtS21A，rtN/S/T/I/V53D，rtY54H，rtS57P，rtL91I，rtS116P，rtL122F，rtF122L，rtN124H，rtY124H，rtH126R，rtY126Q，rtT128N，rtP130Q，rtD131N，rtV134D，rtY135C，rtY141Y/F，rtL145M，rtF151T/F，rtL180M，rtA181T，rtS202G，rtI204V，rtK212R，rtL217R，rtS219A，rtI235I/M，rtN236T，rtN238D，sP120T，sM125T，sS126T，sT127A，sT118R，sM133L/M，sM133T，sF134V，sS143S/T，sD144A，sG145A，sW172Stop，sI195M，sS207R，sY225Y/C，間隔基L97I，間隔基K115R，間隔基H116L，間隔基L128F，間隔基S137G，間隔基R139G，間隔基F142S，rtA97V，rtH126R，rtS135Y，rtM204I，PreS1 N114D，PreS1 T115S，PreS2 F22L，PreS2 V39A，PreS2 P52L，sL89V，sT118A，sF161L，sE164D，sI195M，sI208T，PreS1 E86Q，PreS1 N91K，PreS2 P41H，sQ30K，sP120T，sL176V，sV194F，rtS21A，rtL122F，rtN124H，rtH126R，rtP130Q，rtD131N，rtY135C，rtN/S/T/I/V53D，rtY126Q，rtS202G，rtI204V，rtI235I/M，sM125T，sT127A，sT118R，sM133T，sF134V，sI195M，sS207R，sY225Y/C，rtG172E，rtG174C，rtP177L，rtL180V，rtT184S，sR160N，sE164D，sF170L，sL175L/S，sQ181E/G/Q，sC/W182Y/STOP，sW196L，sW196S，sW196STOP，sM198I，sW199S，sS204T，sY206N，sS210K，sS210R，sL216STOP，sY255F，rtL77L/F，rtL77L/M/V，rtL80I，rtL80V，rtH90N/H，rtS117S/Y，rt125DELrt128，rtQ125K，rtQ125N，rtY126Q，rtL128L/M，rtT128A，rtL132L/M，rtN134G，rtS137T，rtN139H，rtN139K，rtY141Y/STOP，rtV/G142L，rtL147L/W，rtK149R，rtG153E，rtR153Q，rtW153S，rtW153Q，rtF166L，rtI169L，rtF178F/L，rtI187L，rtI187I/V，rtV191I，rtV191V/I，rtN202S，rtS202S/C，rtS202G，rtS213T，rtV/G214E，rtS219A，rtS219P，rtN/Q238H，rtN/S/H238N/K，rtN/S/H/T238/T/A/S/L，rtR242R/K，rtR242R/S，rtN248H，rtI253A，s118-207，s117-120DEL，sI68L/M，sC69F/L，sL109I/L，sG112R，sS17T，sT118R，sK122R，sT123P，sT126S，sT131N，sN131T，sM133K/M，sM133I，sY/F134S，sC139C/G，sK141E，sD144E，sG145R，rtT128T/I，rtL82M，rtT135C，rtT150A，rtV163I，rtT184S，rtA200V，rtF202V，rtS213T，rtQ215H，rtS219A，rtA222T，rtI224S，rtL229M，rtL235I，rtN238S，rtS78T，rt116DEL122，rtI163V，rtL180V，rtE8A，rtV23I，rtD31D/G，rtY53D，rtV58V/I，rtA/S21T，rtV/I/N/S/T53D，rtV/I/N/S/T53Y，rtS/T/N/H/A54Y/H，PreS2L11L/A，PreS2 R17I，DEL PreS2 18-21，PreS2 T30A，PreS2 N54H，sT13T/A，PreS2 Q1V，PreS2 Q1M，rtH90D，rtL/F108L，rtL157L/M，rtA181V，rtV207I，rtP109S，rtN/H/A/S/Q238K，s181M，sP214Q，sF83S，sL173F，sW199L，sI126T，sK160R，sS174N，sA84V，sS210N，sC69STOP/C，sC76Y，si110V/I，sY134N，sW172STOP/W，K32M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；N33D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；P34S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；H35I/L/K/M/F/P/S/T/W/U/V/A/R/N/D/C/Q/E/G/缺失；T37W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P59S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；K60M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；
F61P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；A62R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；V63A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；D83C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/缺失；V84A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；S85T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；A86R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/YV/缺失；Y89V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；H90I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；I/L91K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/缺失；P177S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；F178P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；L179K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；L180K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；A181R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Q183E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；F183P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；T184W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；Y203V/A/R/N/D/C/O/E/G/H/I/L/K/M/F/P/S/T/W/缺失；M204F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；L235K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N236D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；T237W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P237S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；N238D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H238I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；A238R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；S239T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；Q238E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；K239M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；L247K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N248D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H248I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；
F249P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；M250F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；G251H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/缺失；和V251A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；和/或(iii)包括SEQ ID NO1中所述的氨基酸序列或限定HBV聚合酶且在與SEQ ID NO1最佳比對(duì)后具有至少70％相似性序列的氨基酸序列；其中所述藥劑是根據(jù)此前所限定的方法鑒定的。
優(yōu)選地，藥劑可以結(jié)合抗病毒抗性HBV聚合酶的核苷酸結(jié)合口袋。
更優(yōu)選地，抗病毒抗性HBV聚合酶分子定位于根據(jù)表6中所示的原子坐標(biāo)。
另一優(yōu)選實(shí)施方案中，HBV聚合酶的功能活性與HBV復(fù)制相關(guān)。
本發(fā)明這方面的內(nèi)容中，術(shù)語(yǔ)“鑒定的”包括根據(jù)在此限定的方法已經(jīng)分析、設(shè)計(jì)和/或改進(jìn)過(guò)的藥劑。
本發(fā)明的再一方面涉及利用在此所限定方法鑒定的藥劑調(diào)節(jié)HBV聚合酶活性(如抗病毒藥物抗性HBV聚合酶)的用途，尤其是這些藥劑在治療和/或預(yù)防HBV感染表征的病癥中的用途。例如，拮抗劑HBV感染患者的抗病毒治療中特別有用，其中HBV對(duì)現(xiàn)有的抗病毒藥劑，如ADV、LMV、FCV、FTC、ETV、DAPD和DXG是抗性的。
因此，本發(fā)明的另一方面提供了調(diào)節(jié)患者中至少一種與抗病毒藥物抗性HBV聚合酶相關(guān)的功能活性的方法，所述方法包括在足以使所述藥劑與所述HBV聚合酶分子相互作用并抑制或降低其活性的條件下，將有效量的根據(jù)在此所限定方法鑒定的藥劑引入所述患者中一段時(shí)間。
一實(shí)施方案中，該藥劑抑制HBV復(fù)制。
本發(fā)明的這方面包括體內(nèi)治療以及體外培養(yǎng)系統(tǒng)。例如當(dāng)篩選對(duì)抗病毒抗性HBV聚合酶具有拮抗活性的藥劑時(shí)，后者是有利。
仍然是另一方面，本發(fā)明涉及治療和/或預(yù)防HBV感染的方法，所述方法包括在足以使所述藥劑與所述HBV聚合酶分子相互作用并抑制或降低其活性的條件下，將有效量的根據(jù)在此所述方法鑒定的能夠調(diào)節(jié)所述病毒HBV聚合酶活性的藥劑給藥于患者一段時(shí)間。
根據(jù)本發(fā)明給藥于患者的分子還可以連接靶工具如單克隆抗體，其提供了這些分子至靶細(xì)胞的特定傳送。
優(yōu)選實(shí)施方案中，預(yù)防或治療的主體是哺乳動(dòng)物，更優(yōu)選為人。
可以通過(guò)任何常規(guī)方式進(jìn)行以藥物組合物形式的藥劑給藥。藥物組合物的調(diào)節(jié)劑包括當(dāng)以根據(jù)特定情況的量給藥時(shí)呈現(xiàn)治療活性。例如，變化取決于人或動(dòng)物和所選擇的調(diào)節(jié)劑。寬范圍的劑量是可用的?？紤]患者，例如，每公斤體重每天可以給藥約0.01μg至約10g調(diào)節(jié)劑?？梢哉{(diào)節(jié)給藥方案來(lái)提供最佳治療反應(yīng)。例如，可以以每天、每周、每月或其它合適的時(shí)間間隔給藥數(shù)個(gè)分開(kāi)的劑量，或可以通過(guò)病癥需要按比例減少劑量。實(shí)例量包括0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09或0.1μg，1、2、3、4、5、6、7、8、9或10μg；0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9或1mg；1、2、3、4、5、6、7、8、9或10mg，10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99或100mg；100、200、30、400、500、600、700、800、900或1000mg和1、2、3、4、5、6、7、8、9或10g。藥劑可以以藥物學(xué)上可接受的無(wú)毒鹽給藥，如酸加成鹽或例如和鋅、鐵等等的金屬?gòu)?fù)合物(為了本申請(qǐng)的目將其認(rèn)為鹽)。這樣酸加成鹽的示例是鹽酸鹽、氫溴酸鹽、硫酸鹽、磷酸鹽、馬來(lái)酸鹽、乙酸鹽、檸檬酸鹽、苯甲酸鹽、琥珀酸鹽、蘋(píng)果酸鹽、抗壞血酸鹽、酒石酸鹽等等。如果以片劑形式給藥活性成分，片劑可以含有結(jié)合劑如黃芪膠、玉米淀粉或明膠；崩解劑，如藻朊酸；和潤(rùn)滑劑，如硬脂酸鎂。
給藥的途徑包括但不限于，吸入、器官內(nèi)、鼻咽、靜脈內(nèi)、腹膜內(nèi)、皮下、顱內(nèi)、皮內(nèi)、肌肉內(nèi)、眼內(nèi)、鞘內(nèi)、大腦內(nèi)、鼻內(nèi)、灌輸、口服、直腸，通過(guò)IV滴注和植入。優(yōu)選，給藥途徑是允許直接傳送藥劑的途徑。例如，和導(dǎo)致傳送至全身的全身傳送相反，進(jìn)入導(dǎo)氣管的氣溶膠給藥(如通過(guò)噴霧)可以直徑傳送至導(dǎo)氣管區(qū)域。
以治療有效量給藥制劑。治療有效量意思是至少部分獲得所需效果，或延遲待治療特定病癥的發(fā)作、抑制待治療特定病癥的進(jìn)展，或同時(shí)停止待治療特定病癥的發(fā)作或進(jìn)展的必需量。當(dāng)然，這樣的量取決于待治療的特定病癥、病癥的嚴(yán)重程度和個(gè)體患者的參數(shù)，包括年齡、物理狀況、大小、體重和協(xié)同治療。這些因素是本領(lǐng)域普通技術(shù)人員公知的，并且不超過(guò)常規(guī)實(shí)驗(yàn)就可以解決。通常根據(jù)合理的醫(yī)學(xué)判斷優(yōu)選使用最大劑量，即最高的安全劑量。然而，本領(lǐng)域普通技術(shù)人員將理解，因?yàn)獒t(yī)學(xué)原因、物理原因或因?yàn)閷?shí)際上任何其它原因可以給藥較低的劑量或可耐受劑量。
如上所述，制劑的日、周或月劑量可以為約0.01μg/kg每天至1000mg/kg每天。開(kāi)始可以給藥小劑量(0.01-1mg)，接著提高劑量至約1000mg/kg每天。在患者對(duì)該劑量反應(yīng)不足的情況下，可以使用甚至更高的劑量(或通過(guò)不同的、更好定位的傳送途徑給藥有效的更高劑量)至患者耐受力允許的極限?？梢詥蝿┝拷o藥或基于每小時(shí)、每日、每周或每月需要的多劑量給藥。制劑的有效量根據(jù)個(gè)體而改變，但約為0.1μg至約20mg每劑，或者約1μg至約10mg或更優(yōu)選約1μg至5mg。
本發(fā)明另一方面涉及根據(jù)在此所限定的方法鑒定的能夠調(diào)節(jié)至少一種抗病毒藥物抗性HBV聚合酶相關(guān)功能活性的藥劑在制造用于治療和/或預(yù)防HBV感染藥物中的用途。
另一方面，本發(fā)明涉及根據(jù)在此所限定的方法鑒定的藥劑在制造用于調(diào)節(jié)抗病毒藥物抗性HBV聚合酶功能活性藥物中的用途。
再一方面涉及藥劑在調(diào)節(jié)抗病毒藥物抗性HBV聚合酶分子功能活性中的用途，其中所述藥劑是根據(jù)在此所限定的方法鑒定的。
再一方面涉及藥劑在治療和/或預(yù)防HBV感染中的用途，其中所述藥劑是根據(jù)在此所限定的方法鑒定的。
本發(fā)明相關(guān)方面中，接受治療的患者可以是需要治療或預(yù)防的人或動(dòng)物。
在此涉及“治療”和“預(yù)防”時(shí)以其最寬的內(nèi)容來(lái)考慮。術(shù)語(yǔ)“治療”不必需表示將動(dòng)物治療直至完全恢復(fù)。相似地，“預(yù)防”不必意思是患者最終沒(méi)有感染病況。因此，治療和預(yù)防包括特定病況癥狀的緩解或特定病況發(fā)展風(fēng)險(xiǎn)的預(yù)防或其它降低。術(shù)語(yǔ)“預(yù)防”認(rèn)為是降低了特定病況發(fā)作的嚴(yán)重性。“治療”還可以降低現(xiàn)有病況的嚴(yán)重性或急性發(fā)作的頻率。
根據(jù)這些方法，根據(jù)本發(fā)明限定的藥劑可以與一種或多種其它化合物或分子共同給藥?！肮餐o藥”意思是通過(guò)相同或不同途徑同時(shí)給藥相同制劑或兩種不同制劑或通過(guò)相同或不同途徑相繼給藥?！跋嗬^”給藥意思是兩種分子給藥之間的時(shí)間差為數(shù)秒、數(shù)分鐘、數(shù)小時(shí)或數(shù)天。這些分子可以以任何次序給藥。
再一方面，本發(fā)明涉及包括在此所限定的藥劑和一種或多種藥物學(xué)上可接受的載體和/或稀釋劑一起的藥物組合物。
適于可注射使用的主體組合物的藥物形式包括無(wú)菌水溶液(其中是水溶性的)或分散和用于無(wú)菌可注射溶液或分散劑臨時(shí)制備的無(wú)菌粉末或可以是霜?jiǎng)┗蚱渌m于局部應(yīng)用的形式。在制造和儲(chǔ)存條件下必需穩(wěn)定，必需防腐來(lái)對(duì)抗微生物如細(xì)菌和真菌的污染作用。載體可以是溶劑或含有例如水、乙醇、多元醇(例如，乙二醇、丙二醇和液體聚乙二醇等等)及其合適的混合物和植物油的分散介質(zhì)。維持合適的流動(dòng)性，例如，通過(guò)使用涂層如卵磷脂，在分散劑情況中通過(guò)維持所需的粒徑，或通過(guò)使用表面活性劑?？梢酝ㄟ^(guò)各種抗菌和抗真菌劑，例如對(duì)羥基苯甲酸、氯代丁醇、苯酚、山梨酸、硫柳汞等等，來(lái)防止微生物的作用。許多情況下，優(yōu)選包括等滲劑，例如，糖或氯化鈉。通過(guò)在組合物使用延遲吸收的藥劑例如單硬脂酸鋁和明膠來(lái)引起可注射組合物的延長(zhǎng)吸收。
通過(guò)將所需量的活性化合物和各種以上列舉的其它成分摻入合適的溶劑中來(lái)制備無(wú)菌可注射溶液，按照需要，接著無(wú)菌過(guò)濾。通常，通過(guò)將各種無(wú)菌活性成分摻入含有基礎(chǔ)分散介質(zhì)和以上列舉那些所需其它成分的無(wú)菌載體中來(lái)制得分散劑。在用于制備無(wú)菌可注射溶液的無(wú)菌粉末情況中，優(yōu)選的制備方法是產(chǎn)生活性成分粉末的真空干燥和凍干技術(shù)加上其之前無(wú)菌過(guò)濾溶液的任何其他所需成分。
當(dāng)活性成分得到適當(dāng)保護(hù)時(shí)，可以口服，例如，用惰性稀釋劑或用可吸收的可食載體，或可以封裝于硬殼或軟殼明膠膠囊中，或可以壓制成片劑，或可以直接摻入食品或膳食中。為了口服治療服用，活性化合物可以和賦形劑摻在一起并以可消化的片劑、頰含片、錠劑、膠囊、酏劑、懸浮液、糖漿、糯米紙囊劑等等形式來(lái)使用。這樣的組合物和制劑含有至少1％重量的活性化合物。當(dāng)然，組合物和制劑的百分比可以改變并可以方便地為約5至約80％重量單位。這樣治療有用組合物中活性化合物的量使得獲得合適的劑量。根據(jù)本發(fā)明優(yōu)選制備組合物或制劑使得口服劑量單位含有約0.01μg至10mg活性化合物。
片劑、錠劑、丸劑、膠囊等等還可以含有此后所列的成分結(jié)合劑如樹(shù)膠、阿拉伯樹(shù)膠、玉米淀粉或明膠；賦形劑如磷酸二鈣；崩解劑如玉米淀粉、土豆淀粉、藻朊酸等等；潤(rùn)滑劑如硬脂酸鎂；和可以加入甜味劑如蔗糖、乳糖或糖精，或香料如薄荷、冬綠油或櫻桃香料。當(dāng)劑量單位形式是膠囊時(shí)，除了上述類型的原料，其可以含有液體載體。各種其它原料可以作為涂層存在或來(lái)另外修飾劑量單位的物理形式。例如，片劑、丸劑或膠囊可以涂覆蟲(chóng)膠、糖或兩者。糖漿或酏劑可以含有活性化合物、作為甜味劑的蔗糖、作為防腐劑的對(duì)羥基苯甲酸甲酯和對(duì)羥基苯甲酸丙酯、染料和香精如櫻桃或橙子香精。當(dāng)然，制備任何劑量單位形式中所用的任何原料應(yīng)該是藥物學(xué)純的并基本上在所用量中是無(wú)毒性的。此外，活性化合物可以摻入持續(xù)釋放的制劑和劑型中。
還應(yīng)當(dāng)理解本發(fā)明拓寬至三維結(jié)構(gòu)的抗病毒藥物抗性HBV聚合酶分子關(guān)于分析和/或闡明HBV核酸復(fù)制機(jī)理的用途。本發(fā)明進(jìn)一步拓寬至源自其的診斷、治療和/或預(yù)防發(fā)展。
仍然進(jìn)一步理解本發(fā)明拓寬至任何非天然生成形式的抗病毒抗性HBV聚合酶分子。非天然生成形式抗病毒抗性HBV聚合酶分子的實(shí)例特別包括分子的結(jié)晶形式。
如上所述，本發(fā)明涉及用于測(cè)定野生型HBV聚合酶和抗病毒藥物抗性HBV聚合酶之間核酸序列差異性的計(jì)算機(jī)程序產(chǎn)品，包括(1)抗病毒藥物抗性HBV聚合酶或其片段的原子坐標(biāo)作為輸入值接受的編碼；(2)將那些原子坐標(biāo)與野生型HBV聚合酶或其片段的原子坐標(biāo)相比較的編碼；和(3)存儲(chǔ)編碼的計(jì)算機(jī)可讀介質(zhì)。
本發(fā)明的再一方面拓寬至測(cè)定野生型HBV聚合酶和抗病毒藥物抗性HBV聚合酶之間核苷酸序列差異的計(jì)算機(jī)，包括(1)機(jī)器可讀數(shù)據(jù)存儲(chǔ)介質(zhì)，包括用機(jī)器可讀數(shù)據(jù)編碼的數(shù)據(jù)存儲(chǔ)材料，其中所述機(jī)器可讀數(shù)據(jù)包括用于鑒定野生型HBV聚合酶或其片段的原子坐標(biāo)的值；(2)工作存儲(chǔ)器，用于存儲(chǔ)處理所述機(jī)器可讀數(shù)據(jù)的指令并比較包括抗病毒藥物抗性HBV聚合酶原子坐標(biāo)的輸入數(shù)據(jù)的指令；(3)連接于所述工作存儲(chǔ)器和所述機(jī)器可讀數(shù)據(jù)存儲(chǔ)介質(zhì)的中央處理單元，用于處理所述機(jī)器可讀數(shù)據(jù)以比較所述值來(lái)提供參照數(shù)據(jù)庫(kù)的標(biāo)記物鑒定的評(píng)價(jià)；和(4)連接于所述中央處理單元的輸出硬件，用于接收比較的結(jié)果。
這些實(shí)施例的方案列于圖7中，其顯示了包括計(jì)算機(jī)11的系統(tǒng)10，計(jì)算機(jī)包括中央處理器(“CPU”)20，可以是例如RAM(隨機(jī)存取存儲(chǔ)器)或“磁心”存儲(chǔ)器的工作存儲(chǔ)器22，大容量存儲(chǔ)器24(如一個(gè)或多個(gè)磁盤(pán)驅(qū)動(dòng)器或CD-ROM驅(qū)動(dòng)器)，一個(gè)或多個(gè)陰極射線管(“CRT”)顯示終端26，一個(gè)或多個(gè)鍵盤(pán)28，一個(gè)或多個(gè)輸入線30，以及一個(gè)或多個(gè)輸出線40，所有這些通過(guò)通用的雙向系統(tǒng)總線50相互連接。
通過(guò)輸入線30連接計(jì)算機(jī)11的輸入硬件36，可以以各種方式來(lái)執(zhí)行。例如，可以通過(guò)使用由電話線或?qū)Ｓ脭?shù)據(jù)線34連接的調(diào)制解調(diào)器32輸入本發(fā)明的機(jī)器可讀數(shù)據(jù)。可替換地或另外地，輸入硬件36可以包括CD?；蛘?，連接顯示終端26、鍵盤(pán)28的ROM驅(qū)動(dòng)器或磁盤(pán)驅(qū)動(dòng)器24還可以用作輸入裝置。
通過(guò)輸出線40連接計(jì)算機(jī)11的輸出硬件46，可以相似地通過(guò)通用常規(guī)裝置來(lái)執(zhí)行。例如，輸出硬件46可以包括用于顯示如在此所述的合成多核苷酸序列或合成多肽序列的CRT顯示終端26。輸出硬件還可以包括打印機(jī)42，使得可以產(chǎn)生硬拷貝輸出，或磁盤(pán)驅(qū)動(dòng)器24來(lái)存儲(chǔ)系統(tǒng)輸出用于以后的使用。
(1)操作中，CPU20協(xié)調(diào)了各種輸入和輸出裝置36，46的用途，協(xié)調(diào)來(lái)自大量存儲(chǔ)器24的數(shù)據(jù)存取以及進(jìn)入和來(lái)自工作存儲(chǔ)器22的數(shù)據(jù)存取，并測(cè)定數(shù)據(jù)處理步驟的次序。多個(gè)程序可以用來(lái)處理本發(fā)明的機(jī)器可讀數(shù)據(jù)。
圖9顯示了磁性數(shù)據(jù)存儲(chǔ)介質(zhì)100的橫截面，可以用機(jī)器可讀數(shù)據(jù)或一套指令來(lái)編碼，用于設(shè)計(jì)本發(fā)明的合成分子，其可以通過(guò)如圖8的系統(tǒng)10的系統(tǒng)來(lái)進(jìn)行。介質(zhì)100可以是通用軟盤(pán)或硬盤(pán)，具有合適的基質(zhì)101，其可以是通用的和合適的涂層102，其可以是常規(guī)的，在一側(cè)或兩側(cè)，含有磁性結(jié)構(gòu)域(不可見(jiàn))，其極性或方向可以磁性地改變。介質(zhì)100可以還具有開(kāi)口(未顯示)用于接受磁盤(pán)驅(qū)動(dòng)器或其它數(shù)據(jù)存儲(chǔ)裝置24的軸。介質(zhì)100的涂層102的磁性結(jié)構(gòu)域是極性的或方向的，使得以常規(guī)的方式來(lái)編碼，如在此所述的機(jī)器可讀數(shù)據(jù)，用于通過(guò)如圖8的系統(tǒng)10的系統(tǒng)來(lái)闡明。
圖10顯示了光可讀數(shù)據(jù)存儲(chǔ)介質(zhì)110的橫截面，其還可以用這樣的機(jī)器可讀數(shù)據(jù)或一套說(shuō)明來(lái)編碼，用于設(shè)計(jì)本發(fā)明的合成分子，其可以通過(guò)如圖8的系統(tǒng)10的系統(tǒng)來(lái)進(jìn)行。介質(zhì)110可以是常規(guī)的光盤(pán)只讀存儲(chǔ)器(CD-ROM)或可再寫(xiě)基質(zhì)如磁盤(pán)，其是光可讀的和磁光可寫(xiě)的。介質(zhì)100優(yōu)選具有常規(guī)的合適基質(zhì)111，和常規(guī)的合適涂層112，通常為基質(zhì)111的一側(cè)。
如公知的，在CD-ROM的情況中，涂層112是反射的并用多個(gè)槽113壓痕來(lái)編碼機(jī)器可讀數(shù)據(jù)。通過(guò)反射涂層112表面的激光來(lái)閱讀槽的排列。在涂層112的上面提供保護(hù)性涂層114，其優(yōu)選是基本上透明的。
根據(jù)本發(fā)明的另一方面，鑒定了HBV DNA聚合酶中的金屬結(jié)合位點(diǎn)或區(qū)域。聚合酶分子需要金屬離子來(lái)催化。在HIV聚合酶中需要兩個(gè)鎂離子，這些位于天冬氨酸殘基185和186的附近。除了這個(gè)金屬結(jié)合區(qū)域(通過(guò)本模型中的殘基205和206來(lái)限定)，根據(jù)本發(fā)明，鑒定三個(gè)含有組氨酸和酪氨酸殘基簇的區(qū)域。
這些區(qū)域通過(guò)選自以下所列的氨基酸殘基來(lái)限定，包括金屬結(jié)合位點(diǎn)1rtE1、rtH12、rtH13、rtH160和rtA162；金屬結(jié)合位點(diǎn)2rtC-9、rtH-6、rtH90、rtL93、rtH234；金屬結(jié)合位點(diǎn)3rtH197、rtC198、rtH216和rtC213。
這些金屬結(jié)合位點(diǎn)還顯示于圖17、18和19中。
之前已經(jīng)在其它聚合酶蛋白質(zhì)中證明了酪氨酸和組氨酸殘基影響金屬離子的性能且由于它們影響誘導(dǎo)的敏感性和大小，因此對(duì)于活性是重要的(Khan等，Biochem Biophys Res Commun.299(3)438-45，2002；Wulfing等，J Biol Chem.269(4)2895-901，1994)。提出的這些新結(jié)合位點(diǎn)還涉及聚合酶活性或相關(guān)的功能如RNA/DNA結(jié)合或新延長(zhǎng)鏈的鏈轉(zhuǎn)移。這些對(duì)于HBV聚合酶的另外金屬結(jié)合位點(diǎn)之前還沒(méi)有鑒定為抗病毒化合物或診斷劑的目標(biāo)。
因此，本發(fā)明的另一方面涉及HBV聚合酶分離的片段，該片段包括氨基酸選自以下的殘基(i)rtE1、rtH12、rtH13、rtH160和rtA162；(ii)rtC-9、rtH-6、rtH90、rtL93、rtH234；和(iii)rtH197、rtC198、rtH216和rtC213，其中所述片段如圖17、18和19所示的能夠結(jié)合金屬離子，且其中所述片段能夠結(jié)合金屬離子。
更多的實(shí)施方案涉及篩選抗HBV藥劑或診斷劑的方法，所述方法包括鑒定能夠與HBV聚合酶的片段結(jié)合、連接或其它相互作用的化合物，該HBV聚合酶的片段通過(guò)選自以下的氨基酸殘基來(lái)限定(i)rtE1、rtH12、rtH13、rtH160和rtA162；(ii)rtC-9、rtH-6、rtH90、rtL93、rtH234；和(iii)rtH197、rtC198、rtH216和rtC213，其中所述區(qū)域是如圖17、18和19所示的金屬離子結(jié)合位點(diǎn)。
根據(jù)該方法的抗HBV藥劑可以用于疫苗中或作為診斷劑。除了此后的實(shí)施方案，提供的診斷劑包括能夠與HBV聚合酶的片段結(jié)合、連接或其它相互作用的分子，該HBV聚合酶的片段是通過(guò)位于或接近選自以下的氨基酸殘基限定的(i)rtE1、rtH12、rtH13、rtH160和rtA162；(ii)rtC-9、rtH-6、rtH90、rtL93、rtH234；和(iii)rtH197、rtC198、rtH216和rtC213，其中所述區(qū)域是如圖17、18和19所示的金屬離子結(jié)合位點(diǎn)，其中所述區(qū)域是金屬離子結(jié)合位點(diǎn)。作為診斷劑，可以用能夠提供可鑒定信號(hào)的報(bào)告分子來(lái)直接標(biāo)記藥劑，或通過(guò)使用例如抗體或藥劑的其它配體來(lái)鑒定藥劑。
本發(fā)明進(jìn)一步提供了HBV DNA聚合酶中的金屬離子結(jié)合位點(diǎn)在鑒定HBV結(jié)合藥劑或金屬離子結(jié)合抑制劑中的用途，在制造用于治療或檢測(cè)HBV感染的藥物或診斷劑中的用途。
通過(guò)以下非限制性實(shí)施例來(lái)進(jìn)一步描述本發(fā)明。
實(shí)施例1HBV聚合酶的分子模型使用出處同前的Das等，2001，報(bào)道的人免疫缺陷病毒(HIV)逆轉(zhuǎn)錄酶(1RTD)和Georgiadis MM，Jessen SM，Ogata CM，TelesnitskyA，Goff SP，Hendrickson WA.，Structure 3879，1995報(bào)道的小鼠莫洛尼氏白血病毒(MMLV)逆轉(zhuǎn)錄酶(1MML)的晶體結(jié)構(gòu)作為同源模型的模板來(lái)構(gòu)建HBV聚合酶模型。
針對(duì)HIV RT和MMLV RT的序列編號(hào)-25至299的HBV聚合酶原始序列的比對(duì)是用ClustalW原始產(chǎn)生的(Thompson J.D.，Higgins，D.G.和Gibson，T.J.Nucleic Acids Research，1994 224673-4680)，使用BLOSUM 62矩陣接著進(jìn)一步人工比對(duì)。
HBV聚合酶的二級(jí)結(jié)構(gòu)推算是基于5個(gè)獨(dú)立二級(jí)結(jié)構(gòu)推算算法的一致意見(jiàn)GORIV(Garnier J，Gibrat J-F，Robson B MethodsEnzymology 1996 R.F.Doolittle編輯，vol 266，540-553)，PHD(Rost B，Sander C Proc Natl Acad Sci USA.1993年8月15日；90(16)7558-62)，PsiPred(Jones DT.(1999)，J.Mol.Biol.292195-202)，Sspro(G.Pollastri，D.Przybylski，B.Rost和P.Baldi，Proteins，47(2)228-235，2002)，和SOMPA(Geourjon C，Deleage G，Comput Appl Biosci 1995年12月；11(6)681-684)。
使用Sybyl6.9(Tripos Sybyl；版本6.9版1699 South HanleyRoad，St Louis，MO63144，USA)人工構(gòu)建HBV聚合酶的同源模型使得HIV和MMLV RT高序列同源性的區(qū)域具有相同的骨架構(gòu)象，同時(shí)與二級(jí)結(jié)構(gòu)推算一致來(lái)模型化邊側(cè)區(qū)域。在使用Sybyl中的分子動(dòng)態(tài)模擬將模型進(jìn)一步幾何學(xué)最佳化之前還包括雙鏈DNA分子。通過(guò)對(duì)DNA互補(bǔ)鏈進(jìn)行改變將藥物分子人工卸入模型中，使得仍然可以產(chǎn)生最佳堿基配對(duì)。使分子模型溶劑化于81埃立方的水中并接受NAMD分子動(dòng)態(tài)模擬(L Kale，R Skeel，M Bhandarker，R Brunner，A Gursoy，N Krawetz，J Phillips，A Shinozaki，K Varadarajan，和K Schulten，Journal of Computational Physics，151283-312，1999)1納秒用于最終的結(jié)構(gòu)平衡。
實(shí)施例2HBV聚合酶測(cè)定HBV聚合酶的分子模型。模型顯示于圖2中。
實(shí)施例3原子坐標(biāo)HBV聚合酶的原子坐標(biāo)顯示于表6中。
實(shí)施例4LMV抗性L180M和M204V和L180M和M240I
L180已經(jīng)突變成甲硫氨酸，M204已經(jīng)突變成纈氨酸(圖4)。該位阻引起LMV的抗性，因?yàn)槠洳辉倌芫o密地結(jié)合結(jié)合位點(diǎn)。當(dāng)M204突變成異亮氨酸時(shí)，可以看到相同的效果。
L80I亮氨酸80突變成異亮氨酸是相對(duì)保守的突變，然而，異亮氨酸在β碳的分支與γ碳相對(duì)限制了該殘基的移動(dòng)且和亮氨酸相比較降低了其主鏈的適應(yīng)性。因?yàn)榱涟彼?0位于結(jié)合位點(diǎn)手掌/大拇指區(qū)域的連接處，涉及結(jié)合位點(diǎn)一定的屈曲性，與亮氨酸相比較具有降低屈曲能力的異亮氨酸可以部分解釋由該突變引起的藥物抗性。結(jié)果顯示于圖10中。
V173L纈氨酸173至亮氨酸的突變通過(guò)與形成部分結(jié)合位點(diǎn)的苯丙氨酸88相互作用而改變了結(jié)合位點(diǎn)的形狀。較大的亮氨酸占據(jù)的額外空間導(dǎo)致苯丙氨酸的芳環(huán)進(jìn)一步旋轉(zhuǎn)成結(jié)合位點(diǎn)的空穴，因此改變了結(jié)合位點(diǎn)的形狀。提出該結(jié)合位點(diǎn)形狀的改變引起了藥物抗性。結(jié)果顯示于圖11中。
實(shí)施例5ADV抗性A181T丙氨酸181至蘇氨酸的突變能夠在蘇氨酸羥基部分和脯氨酸177的羧基氧之間形成另外的氫鍵。該另外的氫鍵將形成結(jié)構(gòu)域B一部分的螺旋，彎曲并因此改變結(jié)合位點(diǎn)的形狀。提出結(jié)合位點(diǎn)該改變的形狀引起藥物抗性。結(jié)果顯示于圖12中。
N236T天冬酰胺236至蘇氨酸的突變導(dǎo)致失去236和絲氨酸85之間的氫鍵。該氫鍵的失去將導(dǎo)致結(jié)合位點(diǎn)的形狀改變。除了結(jié)合位點(diǎn)這種可能的改變，絲氨酸85直接涉及核苷抑制劑通過(guò)氫鍵和γ磷酸鹽基團(tuán)的結(jié)合。因此Asn236至Thr236的突變通過(guò)結(jié)合位點(diǎn)的改變可以引起藥物抗性。結(jié)果顯示于圖13中。
實(shí)施例6ETV抗性A38E天冬酰胺38至谷氨酸的突變將改變參與核苷結(jié)合的結(jié)構(gòu)域F的形狀。因?yàn)樵诮Y(jié)構(gòu)域F中已經(jīng)存在高濃度的負(fù)電荷殘基，由于這些殘基和負(fù)電荷磷酸基團(tuán)之間不理想的負(fù)/負(fù)電荷相互作用，另外的負(fù)電荷殘基將阻礙ETV的結(jié)合。結(jié)果顯示于圖14中。
T184G該突變與A181T突變相似，因?yàn)閮蓚€(gè)突變都導(dǎo)致螺旋彎曲的改變。高度可彎曲的谷氨酸殘基使結(jié)構(gòu)域B中的螺旋能夠彎曲至更大程度，其依次改變了核苷的結(jié)合位點(diǎn)，導(dǎo)致藥物抗性。
S202I由于異亮氨酸需要更大的空間，蘇氨酸202至異亮氨酸的突變將導(dǎo)致一系列改變。異亮氨酸202突變占據(jù)了結(jié)構(gòu)域B和C之間的另外空間，這在野生型病毒中不存在。異亮氨酸202對(duì)另外空間的需要導(dǎo)致結(jié)構(gòu)域C輕微移動(dòng)向上，而結(jié)構(gòu)域B向下移動(dòng)；這依次改變了引起藥物抗性的結(jié)合位點(diǎn)。結(jié)果顯示于圖15中。
M250V甲硫氨酸250至纈氨酸的突變位于接近于核苷結(jié)合位點(diǎn)的結(jié)構(gòu)域E的轉(zhuǎn)折處。認(rèn)為該突變將影響結(jié)合位點(diǎn)附近的殘基的包裝，并因此引起藥物抗性。
實(shí)施例7HBV聚合酶中金屬結(jié)合位點(diǎn)的鑒定聚合酶分子需要金屬離子用于催化。HBV聚合酶中需要兩個(gè)鎂離子，這些位于天冬氨酸殘基185和186附近。除了該金屬結(jié)合區(qū)域(現(xiàn)有模型中通過(guò)殘基205和206來(lái)限定)，鑒定了三個(gè)含有組氨酸和酪氨酸殘基簇的其他區(qū)域。之前已經(jīng)在其它聚合酶蛋白質(zhì)中證明了酪氨酸和組氨酸殘基能影響金屬離子的性能并因?yàn)樗鼈冇绊懥苏T導(dǎo)的敏感度和大小因此對(duì)于活性是重要的。(Khan等，Biochem Biophys ResCommun.299(3)438-45，2002；Wulfing等，J Biol Chem.269(4)2895-901，1994)。提出的HBV聚合酶模型中的金屬結(jié)合位點(diǎn)顯示于圖17、18和19中。金屬結(jié)合位點(diǎn)1包括殘基rtE1、rtH12、rtH13、rtH160和rtA162；金屬結(jié)合位點(diǎn)2包括殘基rtC-9、rtH-6、rtH90、rtL93、rtH234；金屬結(jié)合位點(diǎn)3包括殘基rtH197、rtC198、rtH216和rtC213。這些新的結(jié)合位點(diǎn)涉及聚合酶活性或相關(guān)的功能如RNA/DNA結(jié)合或新延伸鏈的鏈轉(zhuǎn)移。這些對(duì)于HBV聚合酶的另外的金屬結(jié)合位點(diǎn)之前還沒(méi)有鑒定過(guò)并可以成為抗病毒化合物的靶點(diǎn)。
實(shí)施例8體外抗性測(cè)試選擇突變r(jià)tS85A在抗病毒抗性測(cè)試試驗(yàn)中進(jìn)行測(cè)試，由于(a)其提出的位置接近HBV聚合酶同源模型中的rtN236T和三磷酸結(jié)合位點(diǎn)(b)，在沒(méi)有服用ADV患者中分離的HBV中檢測(cè)出該突變，暗示該突變?cè)诨颊咧凶鳛橹饕膹?fù)制物質(zhì)存在。
(a)在HBV感染克隆中通過(guò)直接位點(diǎn)誘變來(lái)形成突變將載體pBlueac4.5中含有1.3×HBV基因組的質(zhì)粒用作感染HBV的克隆。該克隆已經(jīng)在G1896A具有前核(procore)突變。使用市售試劑盒(QuikChange，Stratagene)根據(jù)制造商的說(shuō)明通過(guò)位點(diǎn)直接誘變來(lái)形成點(diǎn)突變。形成HBV重組編碼逆轉(zhuǎn)錄酶rtS85A。通過(guò)測(cè)序來(lái)證實(shí)質(zhì)粒的核苷酸序列和通過(guò)位點(diǎn)直接誘變產(chǎn)生的點(diǎn)突變，根據(jù)制造商的說(shuō)明使用ABI Prism Big Dye Terminator Cycle Sequencing ReadyReaction試劑盒(Perkin Elmer，Cetus Norwalk，CT)。
(b)用質(zhì)粒DNA轉(zhuǎn)染HepG2細(xì)胞和抗病毒處理在轉(zhuǎn)染之前以約20-40％的鋪滿接種Huh7細(xì)胞，然后生長(zhǎng)16-24小時(shí)。使用Fugene根據(jù)制造商的實(shí)驗(yàn)方案來(lái)轉(zhuǎn)染含有HBV編碼特異性突變的質(zhì)粒DNA。
將ADV和LMV重懸浮于無(wú)菌水中，等分，并在-20℃冰凍來(lái)避免藥物的重復(fù)凍融。每天按需要制備含有ADV或LMV的培養(yǎng)基。實(shí)驗(yàn)中，其中在轉(zhuǎn)染前2小時(shí)開(kāi)始ADV或LMV處理，用HBV質(zhì)粒轉(zhuǎn)染后立即將Huh7細(xì)胞暴露于所示濃度的ADV或LMV中。
(c)HBV復(fù)制中間體的分子分泌的HBV抗原的分析使用從Abbott Laboratories購(gòu)買的藥劑盒(Abbott Park，IL，USA)通過(guò)放射免疫試驗(yàn)和微粒酶免疫試驗(yàn)來(lái)進(jìn)行肝炎Be抗原(HbeAg)和乙肝表面抗原(HbsAg)的檢測(cè)。收集來(lái)自Huh7細(xì)胞的培養(yǎng)基，在6,000g離心除去細(xì)胞碎片，轉(zhuǎn)移至干凈的管中，并存儲(chǔ)于20℃直至分析。以陽(yáng)性對(duì)照的倍數(shù)來(lái)表示HbeAg和HbsAg值。適當(dāng)稀釋培養(yǎng)基樣品使得放射免疫試驗(yàn)結(jié)果各自對(duì)于HbeAg或HbsAg低于陽(yáng)性對(duì)照值。
胞間復(fù)制中間體的檢測(cè)從包括0.5％w/v NP-40的Huh7細(xì)胞裂解緩沖液的細(xì)胞質(zhì)部分中分離HBV核顆粒。用DNA酶處理細(xì)胞質(zhì)提取物，調(diào)節(jié)至10mmol/l McC12并通過(guò)500ng/ml蛋白酶K 37℃孵育1.5小時(shí)來(lái)除去未保護(hù)的DNA。然后使用商業(yè)DNA提取試劑盒如Qiagene(DNA提取)或使用連續(xù)苯酚和氯仿提取物的內(nèi)部方法來(lái)提取樣品中的HBV DNA，通過(guò)乙醇沉淀收集核酸。將核酸重懸浮于50μl/l TE中(10mmol/l Tris，1mmol/l乙二胺四乙酸)或5mmol/l乙二胺四乙酸中，在電泳和DNA印跡分析前通過(guò)OD260規(guī)格化。DNA印跡分析后，使用BioRad Phosphoimager和Quantity One Analysis軟件(BioRad，Hecules California)來(lái)分析DNA印跡的合適曝光。使用來(lái)自Jandel Scientific的TableCurve2D軟件包使密度數(shù)據(jù)適于對(duì)數(shù)劑量反應(yīng)曲線。使用對(duì)數(shù)劑量反應(yīng)等式來(lái)計(jì)算IC50和IC90值以及變化的系數(shù)。
用編碼rtS85A的HBV質(zhì)粒進(jìn)行抗病毒測(cè)試ADV和LMV對(duì)編碼rtS85A的HBV的劑量效果顯示于圖21中，使用ADV(0μM)和LMV(0μM)作為對(duì)照。通過(guò)編碼突變r(jià)tS85A的重組HBV對(duì)ADV存在降低的敏感度。HBV前核突變對(duì)ADV具有0.43μM的IC50，對(duì)LMV具有0.005μM的IC50。相反，編碼另外的rtS85A的突變對(duì)于LMV具有0.01μM的IC50，對(duì)于ADV具有5-10μM的IC50。
表6原子坐標(biāo)HBV聚合酶模型_040504_a1ATOM 1 NGLY A975 9.098 -21.241 2.066 1.00 1.00NATOM 2 CA GLY A975 8.102 -20.156 1.866 1.00 1.00CATOM 3 CGLY A975 8.475 -19.295 0.703 1.00 1.00CATOM 4 OGLY A975 9.547 -19.538 0.180 1.00 1.00OATOM 5 HA2 GLY A975 8.160 -19.464 2.700 1.00 1.00HATOM 6 HA1 GLY A975 7.068 -20.429 1.711 1.00 1.00HATOM 7 HN GLY A975 10.068 -21.038 2.032 1.00 1.00HATOM 8 HGLY A975 8.831 -22.032 2.624 1.00 1.00HATOM 9 NPRO A976 7.694 -18.239 0.381 1.00 1.00NATOM 10 CA PRO A976 8.239 -17.093 -0.391 1.00 1.00CATOM 11 CPRO A976 9.103 -16.394 0.644 1.00 1.00CATOM 12 OPRO A976 8.839 -15.286 1.103 1.00 1.00OATOM 13 CB PRO A976 6.968 -16.248 -0.736 1.00 1.00CATOM 14 CG PRO A976 6.153 -16.498 0.584 1.00 1.00CATOM 15 CD PRO A976 6.316 -18.040 0.847 1.00 1.00CATOM 16 HA PRO A976 8.746 -17.334 -1.341 1.00 1.00HATOM 17 HD2 PRO A976 5.743 -18.680 0.172 1.00 1.00HATOM 18 HD1 PRO A976 6.032 -18.268 1.873 1.00 1.00HATOM 19 HG2 PRO A976 5.092 -16.273 0.332 1.00 1.00HATOM 20 HG1 PRO A976 6.431 -15.956 1.524 1.00 1.00HATOM 21 HB1 PRO A976 6.340 -16.596 -1.618 1.00 1.00HATOM 22 HB2 PRO A976 7.130 -15.172 -0.885 1.00 1.00HATOM 23 NCYS A977 10.213 -17.040 1.020 1.00 1.00NATOM 24 CA CYS A977 10.934 -16.779 2.278 1.00 1.00CATOM 25 CCYS A977 11.315 -18.145 2.923 1.00 1.00CATOM 26 OCYS A977 10.624 -19.138 2.692 1.00 1.00OATOM 27 CB CYS A977 10.232 -16.076 3.452 1.00 1.00CATOM 28 SG CYS A977 8.579 -16.705 3.742 1.00 1.00SATOM 29 HA CYS A977 11.884 -16.200 2.086 1.00 1.00HATOM 30 HB1 CYS A977 10.119 -15.007 3.159 1.00 1.00HATOM 31 HB2 CYS A977 10.873 -16.007 4.345 1.00 1.00HATOM 32 HG CYS A977 8.328 -16.030 4.413 1.00 1.00HATOM 33 HN CYS A977 10.586 -17.761 0.446 1.00 1.00HATOM 34 NTRP A978 12.404 -18.253 3.753 1.00 1.00NATOM 35 CA TRP A978 12.903 -19.526 4.280 1.00 1.00CATOM 36 CTRP A978 12.971 -19.279 5.751 1.00 1.00CATOM 37 OTRP A978 14.045 -19.317 6.312 1.00 1.00OATOM 38 CB TRP A978 14.210 -19.696 3.508 1.00 1.00CATOM 39 CG TRP A978 13.858 -19.779 2.007 1.00 1.00CATOM 40 CD1 TRP A978 14.255 -18.931 1.034 1.00 1.00C
ATOM 41 CD2 TRP A97813.135 -20.910 1.361 1.00 1.00CATOM 42 NE1 TRP A97813.746 -19.324 -0.125 1.00 1.00NATOM 43 CE2 TRP A97813.011 -20.448 0.067 1.00 1.00CATOM 44 CE3 TRP A97812.659 -22.140 1.784 1.00 1.00CATOM 45 CZ2 TRP A97812.224 -21.127 -0.872 1.00 1.00CATOM 46 CZ3 TRP A97811.866 -22.882 0.854 1.00 1.00CATOM 47 CH2 TRP A97811.660 -22.335 -0.450 1.00 1.00CATOM 48 HA TRP A97812.303 -20.426 4.162 1.00 1.00HATOM 49 HB1 TRP A97814.781 -20.559 3.898 1.00 1.00HATOM 50 HB2 TRP A97814.787 -18.761 3.703 1.00 1.00HATOM 51 HE1 TRP A97813.851 -18.871 -1.036 1.00 1.00HATOM 52 HD1 TRP A97814.890 -18.065 1.234 1.00 1.00HATOM 53 HZ2 TRP A97812.028 -20.755 -1.865 1.00 1.00HATOM 54 HH2 TRP A97811.070 -22.901 -1.196 1.00 1.00HATOM 55 HZ3 TRP A97811.510 -23.880 1.096 1.00 1.00HATOM 56 HE3 TRP A97812.886 -22.518 2.785 1.00 1.00HATOM 57 HN TRP A97812.874 -17.448 4.099 1.00 1.00HATOM 58 N TRP A97911.812 -18.977 6.404 1.00 1.00NATOM 59 CA TRP A97911.780 -18.720 7.806 1.00 1.00CATOM 60 C TRP A97910.375 -18.911 8.325 1.00 1.00CATOM 61 O TRP A9799.652 -19.534 7.591 1.00 1.00OATOM 62 CB TRP A97912.411 -17.325 8.050 1.00 1.00CATOM 63 CG TRP A97911.563 -16.098 7.828 1.00 1.00CATOM 64 CD1 TRP A97910.474 -15.996 7.075 1.00 1.00CATOM 65 CD2 TRP A97911.906 -14.754 8.421 1.00 1.00CATOM 66 NE1 TRP A97910.179 -14.746 7.060 1.00 1.00NATOM 67 CE2 TRP A97910.933 -13.967 7.829 1.00 1.00CATOM 68 CE3 TRP A97912.887 -14.240 9.249 1.00 1.00CATOM 69 CZ2 TRP A97910.853 -12.583 8.059 1.00 1.00CATOM 70 CZ3 TRP A97912.875 -12.856 9.348 1.00 1.00CATOM 71 CH2 TRP A97911.857 -12.015 8.842 1.00 1.00CATOM 72 HA TRP A97912.390 -19.555 8.245 1.00 1.00HATOM 73 H31 TRP A97913.281 -17.243 7.359 1.00 1.00HATOM 74 HB2 TRP A97912.885 -17.287 9.026 1.00 1.00HATOM 75 HE1 TRP A9799.422 -14.396 6.502 1.00 1.00HATOM 76 HD1 TRP A97910.001 -16.788 6.498 1.00 1.00HATOM 77 HZ2 TRP A97910.044 -12.046 7.630 1.00 1.00HATOM 78 HH2 TRP A97911.868 -10.941 9.048 1.00 1.00HATOM 79 HZ3 TRP A97913.717 -12.380 9.866 1.00 1.00HATOM 80 HE3 TRP A97913.638 -14.910 9.707 1.00 1.00HATOM 81 HN TRP A97910.934 -18.878 5.904 1.00 1.00HATOM 82 N LEU A9809.949 -18.352 9.492 1.00 1.00NATOM 83 CA LEU A9808.536 -18.570 9.907 1.00 1.00CATOM 84 C LEU A9807.678 -17.767 8.911 1.00 1.00CATOM 85 O LEU A9808.165 -16.797 8.351 1.00 1.00OATOM 86 CB LEU A9808.093 -18.124 11.304 1.00 1.00CATOM 87 CG LEU A9808.558 -19.071 12.431 1.00 1.00CATOM 88 CD1 LEU A9807.859 -20.460 12.488 1.00 1.00CATOM 89 CD2 LEU A98010.106 -19.229 12.414 1.00 1.00CATOM 90 HA LEU A9808.217 -19.654 9.833 1.00 1.00HATOM 91 HB1 LEU A9807.002 -18.077 11.361 1.00 1.00HATOM 92 HB2 LEU A9808.499 -17.104 11.459 1.00 1.00H
ATOM93 HG LEU A980 8.335 -18.497 13.389 1.00 1.00 HATOM94 HD21 LEU A980 10.686 -18.251 12.496 1.00 1.00 HATOM95 HD22 LEU A980 10.412 -19.746 11.469 1.00 1.00 HATOM96 HD23 LEU A980 10.400 -19.792 13.299 1.00 1.00 HATOM97 HD11 LEU A980 6.770 -20.393 12.300 1.00 1.00 HATOM98 HD12 LEU A980 8.089 -20.994 13.463 1.00 1.00 HATOM99 HD13 LEU A980 8.273 -21.106 11.703 1.00 1.00 HATOM100 HN LEU A980 10.501 -17.727 10.060 1.00 1.00 HATOM101 NGLN A981 6.356 -18.115 8.7991.00 1.00 NATOM102 CA GLN A981 5.528 -17.601 7.6751.00 1.00 CATOM103 CGLN A981 4.223 -17.145 8.2431.00 1.00 CATOM104 OGLN A981 3.245 -17.266 7.5321.00 1.00 OATOM105 CB GLN A981 5.310 -18.750 6.6391.00 1.00 CATOM106 CG GLN A981 6.619 -19.544 6.2861.00 1.00 CATOM107 CD GLN A981 6.335 -20.618 5.2591.00 1.00 CATOM108 OE1 GLN A981 6.635 -20.365 4.1051.00 1.00 OATOM109 NE2 GLN A981 5.814 -21.810 5.6571.00 1.00 NATOM110 HA GLN A981 5.976 -16.723 7.1941.00 1.00 HATOM111 HB1 GLN A981 4.962 -18.353 5.6571.00 1.00 HATOM112 HB2 GLN A981 4.561 -19.485 6.9571.00 1.00 HATOM113 HG1 GLN A981 7.096 -19.978 7.1891.00 1.00 HATOM114 HG2 GLN A981 7.383 -18.836 5.8801.00 1.00 HATOM115 HE22 GLN A981 5.601 -22.529 4.9741.00 1.00 HATOM116 HE21 GLN A981 5.512 -22.039 6.5911.00 1.00 HATOM117 HN GLN A981 5.961 -18.762 9.3991.00 1.00 HATOM118 NPHE A982 4.105 -16.633 9.4721.00 1.00 NATOM119 CA PHE A982 2.784 -16.333 10.045 1.00 1.00 CATOM120 CPHE A982 2.726 -15.137 10.982 1.00 1.00 CATOM121 OPHE A982 2.312 -15.283 12.123 1.00 1.00 OATOM122 CB PHE A982 2.224 -17.590 10.765 1.00 1.00 CATOM123 CG PHE A982 2.227 -18.789 9.7421.00 1.00 CATOM124 CD1 PHE A982 1.206 -18.844 8.8161.00 1.00 CATOM125 CD2 PHE A982 3.225 -19.759 9.7801.00 1.00 CATOM126 CE1 PHE A982 1.288 -19.743 7.7471.00 1.00 CATOM127 CE2 PHE A982 3.160 -20.822 8.8551.00 1.00 CATOM128 CZPHE A982 2.212 -20.803 7.8211.00 1.00 CATOM129 HAPHE A982 2.169 -16.042 9.1961.00 1.00 HATOM130 HB1 PHE A982 1.207 -17.356 11.119 1.00 1.00 HATOM131 HB2 PHE A982 2.838 -17.955 11.617 1.00 1.00 HATOM132 HD2 PHE A982 4.060 -19.775 10.510 1.00 1.00 HATOM133 HE2 PHE A982 3.844 -21.670 8.8661.00 1.00 HATOM134 HZPHE A982 2.191 -21.608 7.0731.00 1.00 HATOM135 HE1 PHE A982 0.618 -19.693 6.8901.00 1.00 HATOM136 HD1 PHE A982 0.356 -18.149 8.9151.00 1.00 HATOM137 HNPHE A982 4.885 -16.435 10.024 1.00 1.00 HATOM138 N ARG A983 2.979 -13.908 10.540 1.00 1.00 NATOM139 CAARG A983 2.796 -12.715 11.368 1.00 1.00 CATOM140 C ARG A983 1.340 -12.382 11.184 1.00 1.00 CATOM141 O ARG A983 1.082 -11.344 10.610 1.00 1.00 OATOM142 CBARG A983 3.793 -11.545 11.056 1.00 1.00 CATOM143 CGARG A983 5.246 -11.751 11.711 1.00 1.00 CATOM144 CDARG A983 6.078 -12.805 10.867 1.00 1.00 C
ATOM145 NE ARG A983 7.506 -12.891 11.153 1.00 1.00 NATOM146 CZ ARG A983 8.378 -13.721 10.578 1.00 1.00 CATOM147 NH1 ARG A983 8.002 -14.619 9.726 1.00 1.00 NATOM148 NH2 ARG A983 9.624 -13.679 10.845 1.00 1.00 NATOM149 HA ARG A983 2.885 -12.968 12.437 1.00 1.00 HATOM150 HB1 ARG A983 3.335 -10.663 11.481 1.00 1.00 HATOM151 HB2 ARG A983 3.883 -11.340 9.959 1.00 1.00 HATOM152 HG1 ARG A983 5.151 -12.042 12.764 1.00 1.00 HATOM153 HG2 ARG A983 5.836 -10.850 11.621 1.00 1.00 HATOM154 HD1 ARG A983 6.046 -12.546 9.805 1.00 1.00 HATOM155 HD2 ARG A983 5.652 -13.830 11.091 1.00 1.00 HATOM156 HE ARG A983 7.841 -12.217 11.851 1.00 1.00 HATOM157 HH12 ARG A983 8.675 -15.220 9.280 1.00 1.00 HATOM158 HH11 ARG A983 7.057 -14.760 9.4.02 1.00 1.00 HATOM159 HH22 ARG A983 10.306 -14.333 10.437 1.00 1.00 HATOM160 HH21 ARG A983 9.927 -13.118 11.581 1.00 1.00 HATOM161 HN ARG A983 3.300 -13.774 9.618 1.00 1.00 HATOM162 NASN A984 0.370 -13.280 11.623 1.00 1.00 NATOM163 CA ASN A984-1.048 -12.964 11.440 1.00 1.00 CATOM164 CASN A984-1.253 -11.669 12.172 1.00 1.00 CATOM165 OASN A984-0.487 -11.361 13.084 1.00 1.00 OATOM166 CB ASN A984-1.992 -14.031 12.086 1.00 1.00 CATOM167 CG ASN A984-1.687 -15.381 11.509 1.00 1.00 CATOM168 OD1 ASN A984-0.957 -16.111 12.155 1.00 1.00 OATOM169 ND2 ASN A984-2.127 -15.663 10.252 1.00 1.00 NATOM170 HA ASN A984-1.166 -12.815 10.323 1.00 1.00 HATOM171 HB1 ASN A984-3.041 -13.772 11.961 1.00 1.00 HATOM172 HB2 ASN A984-1.801 -14.115 13.177 1.00 1.00 HATOM173 HD22 ASN A984-1.772 -16.510 9.835 1.00 1.00 HATOM174 HD21 ASN A984-2.660 -15.012 9.719 1.00 1.00 HATOM175 HN ASN A984 0.608 -14.108 12.210 1.00 1.00 HATOM176 NSER A985-2.310 -10.838 11.864 1.00 1.00 NATOM177 CA SER A985-2.464 -9.571 12.582 1.00 1.00 CATOM178 CSER A985-3.890 -9.044 12.469 1.00 1.00 CATOM179 OSER A985-4.570 -8.908 13.484 1.00 1.00 OATOM180 CB SER A985-1.550 -8.495 12.070 1.00 1.00 CATOM181 OG SER A985-1.775 -8.276 10.692 1.00 1.00 OATOM182 HA SER A985-2.364 -9.676 13.679 1.00 1.00 HATOM183 HB1 SER A985-0.497 -8.698 12.362 1.00 1.00 HATOM184 HB2 SER A985-1.799 -7.533 12.509 1.00 1.00 HATOM185 HG SER A985-1.421 -9.033 10.207 1.00 1.00 HATOM186 HN SER A985-2.933 -11.139 11.181 1.00 1.00 HATOM187 NLYS A986-4.472 -8.771 11.259 1.00 1.00 NATOM188 CA LYS A986-5.841 -8.195 11.267 1.00 1.00 CATOM189 CLYS A986-6.890 -9.331 11.210 1.00 1.00 CATOM190 OLYS A986-6.565 -10.364 10.644 1.00 1.00 OATOM191 CB LYS A986-6.052 -7.401 9.923 1.00 1.00 CATOM192 CG LYS A986-5.447 -5.985 10.068 1.00 1.00 CATOM193 CD LYS A986-3.901 -6.078 10.176 1.00 1.00 CATOM194 CE LYS A986-3.139 -4.722 9.880 1.00 1.00 CATOM195 NZ LYS A986-3.423 -3.698 10.894 1.00 1.00 NATOM196 HA LYS A986-6.043 -7.510 12.083 1.00 1.00 H
ATOM197 HB1 LYS A986-5.699 -7.987 9.129 1.00 1.00HATOM198 HB2 LYS A986-7.168 -7.243 9.805 1.00 1.00HATOM199 HG1 LYS A986-5.756 -5.471 10.982 1.00 1.00HATOM200 HG2 LYS A986-5.724 -5.419 9.167 1.00 1.00HATOM201 HD1 LYS A986-3.598 -6.761 9.353 1.00 1.00HATOM202 HD2 LYS A986-3.593 -6.452 11.162 1.00 1.00HATOM203 HE1 LYS A986-3.490 -4.323 8.919 1.00 1.00HATOM204 HE2 LYS A986-2.078 -4.881 9.845 1.00 1.00HATOM205 HZ1 LYS A986-3.115 -2.702 10.657 1.00 1.00HATOM206 HZ2 LYS A986-2.954 -3.856 11.827 1.00 1.00HATOM207 HZ3 LYS A986-4.500 -3.527 10.979 1.00 1.00HATOM208 HN LYS A986-4.013 -8.934 10.416 1.00 1.00HATOM209 N PRO A987-8.126 -9.236 11.778 1.00 1.00NATOM210 CA PRO A987-9.006 -10.400 11.720 1.00 1.00CATOM211 C PRO A987-9.613 -10.588 10.350 1.00 1.00CATOM212 O PRO A987-10.763 -10.220 10.160 1.00 1.00OATOM213 CB PRO A987-9.915 -10.077 12.949 1.00 1.00CATOM214 CG PRO A987-10.027 -8.545 12.833 1.00 1.00CATOM215 CD PRO A987-8.590 -8.066 12.478 1.00 1.00CATOM216 HA PRO A987-8.450 -11.343 11.970 1.00 1.00HATOM217 HD2 PRO A987-8.531 -7.158 11.853 1.00 1.00HATOM218 HD1 PRO A987-7.999 -8.031 13.403 1.00 1.00HATOM219 HG2 PRO A987-10.367 -8.061 13.786 1.00 1.00HATOM220 HG1 PRO A987-10.725 -8.284 11.979 1.00 1.00HATOM221 HB1 PRO A987-9.293 -10.308 13.848 1.00 1.00HATOM222 HB2 PRO A987-10.875 -10.546 13.010 1.00 1.00HATOM223 N CYS A988-8.819 -11.183 9.400 1.00 1.00NATOM224 CA CYS A988-9.371 -11.366 7.995 1.00 1.00CATOM225 C CYS A988-9.853 -10.019 7.328 1.00 1.00CATOM226 O CYS A988-9.225 -9.570 6.395 1.00 1.00OATOM227 CB CYS A988-10.478 -12.406 7.852 1.00 1.00CATOM228 SG CYS A988-9.925 -14.093 7.858 1.00 1.00SATOM229 HA CYS A988-8.585 -11.752 7.376 1.00 1.00HATOM230 HB1 CYS A988-10.883 -12.287 6.861 1.00 1.00HATOM231 H32 CYS A988-11.233 -12.178 8.622 1.00 1.00HATOM232 HG CYS A988-10.804 -14.532 7.549 1.00 1.00HATOM233 HN CYS A988-7.862 -11.354 9.618 1.00 1.00HATOM234 N SER A989-10.944 -9.439 7.817 1.00 1.00NATOM235 CA SER A989-11.548 -8.248 7.159 1.00 1.00CATOM236 C SER A989-11.700 -8.450 5.645 1.00 1.00CATOM237 O SER A989-12.801 -8.795 5.247 1.00 1.00OATOM238 CB SER A989-10.678 -7.018 7.508 1.00 1.00CATOM239 OG SER A989-10.707 -6.766 8.937 1.00 1.00OATOM240 HA SER A989-12.526 -8.132 7.678 1.00 1.00HATOM241 HB1 SER A989-11.273 -6.158 7.107 1.00 1.00HATOM242 HB2 SER A989-9.661 -7.017 7.080 1.00 1.00HATOM243 HG SER A989-10.409 -7.536 9.410 1.00 1.00HATOM244 HN SER A989-11.357 -9.790 8.665 1.00 1.00HATOM245 N ASP A990-10.653 -8.340 4.750 1.00 1.00NATOM246 CA ASP A990-10.799 -8.615 3.268 1.00 1.00CATOM247 C ASP A990-9.684 -9.479 2.765 1.00 1.00CATOM248 O ASP A990-9.266 -9.300 1.629 1.00 1.00O
ATOM249 CB ASP A990 -10.994 -7.278 2.552 1.00 1.00 CATOM250 CG ASP A990 -11.870 -7.403 1.302 1.00 1.00 CATOM251 OD1 ASP A990 -13.139 -7.167 1.381 1.00 1.00 OATOM252 OD2 ASP A990 -11.324 -7.833 0.273 1.00 1.00 OATOM253 HA ASP A990 -11.682 -9.234 3.115 1.00 1.00 HATOM254 HB1 ASP A990 -10.020 -6.828 2.325 1.00 1.00 HATOM255 HB2 ASP A990 -11.585 -6.562 3.234 1.00 1.00 HATOM256 HN ASP A990 -9.673 -8.229 5.070 1.00 1.00 HATOM257 N TYR A991 -9.296 -10.445 3.615 1.00 1.00 NATOM258 CA TYR A991 -8.287 -11.480 3.236 1.00 1.00 CATOM259 C TYR A991 -6.926 -10.954 2.710 1.00 1.00 CATOM260 O TYR A991 -5.839 -11.105 3.245 1.00 1.00 OATOM261 CB TYR A991 -8.950 -12.475 2.208 1.00 1.00 CATOM262 CG TYR A991 -10.298 -12.880 2.832 1.00 1.00 CATOM263 CD1 TYR A991 -10.351 -13.931 3.745 1.00 1.00 CATOM264 CD2 TYR A991 -11.465 -12.205 2.437 1.00 1.00 CATOM265 CE1 TYR A991 -11.595 -14.375 4.248 1.00 1.00 CATOM266 CE2 TYR A991 -12.642 -12.571 3.062 1.00 1.00 CATOM267 CZ TYR A991 -12.732 -13.582 4.034 1.00 1.00 CATOM268 OH TYR A991 -13.907 -13.771 4.790 1.00 1.00 OATOM269 HA TYR A991 -7.956 -12.077 4.124 1.00 1.00 HATOM270 HB2 TYR A991 -8.335 -13.345 2.041 1.00 1.00 HATOM271 HB1 TYR A991 -9.170 -12.024 1.253 1.00 1.00 HATOM272 HD2 TYR A991 -11.470 -11.486 1.604 1.00 1.00 HATOM273 HE2 TYR A991 -13.504 -11.980 2.760 1.00 1.00 HATOM274 HE1 TYR A991 -11.699 -15.301 4.793 1.00 1.00 HATOM275 HD1 TYR A991 -9.448 -14.408 4.025 1.00 1.00 HATOM276 HH TYR A991 -13.778 -14.303 5.583 1.00 1.00 HATOM277 HN TYR A991 -9.794 -10.612 4.496 1.00 1.00 HATOM278 N CYS A992 -6.938 -10.246 1.549 1.00 1.00 NATOM279 CA CYS A992 -5.661 -9.753 1.042 1.00 1.00 CATOM280 C CYS A992 -5.042 -8.756 1.934 1.00 1.00 CATOM281 O CYS A992 -3.817 -8.694 1.938 1.00 1.00 OATOM282 CB CYS A992 -5.774 -9.219 -0.409 1.00 1.00 CATOM283 SG CYS A992 -4.078 -8.786 -1.022 1.00 1.00 SATOM284 HA CYS A992 -4.927 -10.570 0.998 1.00 1.00 HATOM285 HB1 CYS A992 -6.423 -8.358 -0.502 1.00 1.00 HATOM286 HB2 CYS A992 -6.183 -10.002 -1.123 1.00 1.00 HATOM287 H4 CYS A992 -4.051 -7.962 -0.506 1.00 1.00 HATOM288 HN CYS A992 -7.783 -10.051 1.063 1.00 1.00 HATOM289 N LEU A993 -5.708 -7.900 2.699 1.00 1.00 NATOM290 CA LEU A993 -4.931 -6.981 3.584 1.00 1.00 CATOM291 C LEU A993 -4.006 -7.727 4.503 1.00 1.00 CATOM292 O LEU A993 -2.983 -7.197 4.952 1.00 1.00 OATOM293 CB LEU A993 -5.755 -5.795 4.079 1.00 1.00 CATOM294 CG LEU A993 -6.872 -6.064 5.130 1.00 1.00 CATOM295 CD1 LEU A993 -6.247 -6.740 6.375 1.00 1.00 CATOM296 CD2 LEU A993 -7.701 -4.786 5.439 1.00 1.00 CATOM297 HA LEU A993 -4.239 -6.443 2.929 1.00 1.00 HATOM298 HB1 LEU A993 -6.247 -5.367 3.168 1.00 1.00 HATOM299 HB2 LEU A993 -5.033 -5.063 4.537 1.00 1.00 HATOM300 HG LEU A993 -7.475 -6.810 4.641 1.00 1.00 H
ATOM301 HD21 LEU A993-8.008 -4.3674.484 1.00 1.00 HATOM302 HD22 LEU A993-7.104 -4.0345.935 1.00 1.00 HATOM303 HD23 LEU A993-8.507 -5.0696.022 1.00 1.00 HATOM304 HD11 LEU A993-5.894 -7.7596.203 1.00 1.00 HATOM305 HD12 LEU A993-7.002 -6.7627.187 1.00 1.00 HATOM306 HD13 LEU A993-5.412 -6.1526.774 1.00 1.00 HATOM307 HN LEU A993-6.697 -7.9682.796 1.00 1.00 HATOM308 NSER A994-4.399 -8.9534.875 1.00 1.00 NATOM309 CA SER A994-3.499 -9.8155.622 1.00 1.00 CATOM310 CSER A994-2.420 -10.265 4.652 1.00 1.00 CATOM311 OSER A994-1.250 -10.269 4.986 1.00 1.00 OATOM312 CB SER A994-4.271 -10.985 6.296 1.00 1.00 CATOM313 OG SER A994-3.331 -11.707 7.161 1.00 1.00 OATOM314 HA SER A994-3.102 -9.2086.457 1.00 1.00 HATOM315 HB1 SER A994-4.675 -11.655 5.535 1.00 1.00 HATOM316 HB2 SER A994-5.075 -10.513 6.901 1.00 1.00 HATOM317 HG SER A994-3.713 -12.379 7.719 1.00 1.00 HATOM318 HN SER A994-5.256 -9.3984.569 1.00 1.00 HATOM319 NHIE A995-2.775 -10.642 3.397 1.00 1.00 NATOM320 CA HIE A995-1.656 -10.790 2.414 1.00 1.00 CATOM321 CHIE A995-0.735 -9.5622.453 1.00 1.00 CATOM322 OHIE A995 0.465 -9.7672.467 1.00 1.00 OATOM323 CB HIE A995-1.911 -11.029 0.873 1.00 1.00 CATOM324 CG HIE A995-2.366 -12.414 0.468 1.00 1.00 CATOM325 ND1 HIE A995-2.546 -12.824 -0.932 1.00 1.00 NATOM326 CD2 HIE A995-2.825 -13.476 1.162 1.00 1.00 CATOM327 CE1 HIE A995-2.989 -14.014 -0.959 1.00 1.00 CATOM328 NE2 HIE A995-3.171 -14.382 0.287 1.00 1.00 NATOM329 HA HIE A995-1.131 -11.692 2.792 1.00 1.00 HATOM330 HB1 HIE A995-2.554 -10.236 0.493 1.00 1.00 HATOM331 HB2 HIE A995-0.951 -11.012 0.413 1.00 1.00 HATOM332 HD2 HIE A995-2.954 -13.634 2.228 1.00 1.00 HATOM333 HE2 HIE A995-3.514 -15.315 0.582 1.00 1.00 HATOM334 HE1 HIE A995-3.176 -14.614 -1.833 1.00 1.00 HATOM335 HN HIE A995-3.757 -10.856 3.165 1.00 1.00 HATOM336 NILE A996-1.238 -8.3202.478 1.00 1.00 NATOM337 CA ILE A996-0.333 -7.1972.482 1.00 1.00 CATOM338 CILE A996 0.493 -7.3373.749 1.00 1.00 CATOM339 OILE A996 1.732 -7.1703.672 1.00 1.00 OATOM340 CB ILE A996-1.046 -5.7802.448 1.00 1.00 CATOM341 CG1 ILE A996-1.727 -5.5901.063 1.00 1.00 CATOM342 CG2 ILE A996 0.027 -4.6642.711 1.00 1.00 CATOM343 CD1 ILE A996-2.657 -4.3330.923 1.00 1.00 CATOM344 HA ILE A996 0.390 -7.2291.669 1.00 1.00 HATOM345 HB ILE A996-1.793 -5.8053.293 1.00 1.00 HATOM346 HG11 ILE A996-2.387 -6.4470.825 1.00 1.00 HATOM347 HG12 ILE A996-0.881 -5.4740.385 1.00 1.00 HATOM348 HD11 ILE A996-3.465 -4.3281.687 1.00 1.00 HATOM349 HD12 ILE A996-3.110 -4.393 -0.023 1.00 1.00 HATOM350 HD13 ILE A996-2.099 -3.4130.981 1.00 1.00 HATOM351 HG21 ILE A996 0.425 -4.8163.711 1.00 1.00 HATOM352 HG22 ILE A996-0.426 -3.6522.616 1.00 1.00 H
ATOM353 HG23 ILE A996 0.807 -4.7461.980 1.00 1.00 HATOM354 HN ILE A996 -2.229 -8.1052.534 1.00 1.00 HATOM355 NVAL A997 -0.096 -7.5894.917 1.00 1.00 NATOM356 CA VAL A997 0.794 -7.7436.053 1.00 1.00 CATOM357 CVAL A997 1.783 -8.8975.798 1.00 1.00 CATOM358 OVAL A997 2.974 -8.6265.799 1.00 1.00 OATOM359 CB VAL A997 0.029 -7.9007.429 1.00 1.00 CATOM360 CG1 VAL A997 1.072 -8.0978.607 1.00 1.00 CATOM361 CG2 VAL A997 -0.763 -6.6067.909 1.00 1.00 CATOM362 HA VAL A997 1.363 -6.8346.137 1.00 1.00 HATOM363 HB VAL A997 -0.708 -8.6757.338 1.00 1.00 HATOM364 HG11 VAL A997 1.672 -9.0918.459 1.00 1.00 HATOM365 HG12 VAL A997 0.584 -8.1059.574 1.00 1.00 HATOM366 HG13 VAL A997 1.714 -7.2788.694 1.00 1.00 HATOM367 HG21 VAL A997 -0.238 -5.6287.797 1.00 1.00 HATOM368 HG22 VAL A997 -1.156 -6.6688.928 1.00 1.00 HATOM369 HG23 VAL A997 -1.621 -6.5747.157 1.00 1.00 HATOM370 HN VAL A997 -1.082 -7.7315.024 1.00 1.00 HATOM371 NASN A998 1.272 -10.137 5.620 1.00 1.00 NATOM372 CA ASN A998 2.188 -11.299 5.428 1.00 1.00 CATOM373 CASN A998 3.273 -10.974 4.449 1.00 1.00 CATOM374 OASN A998 4.451 -11.167 4.679 1.00 1.00 OATOM375 CB ASN A998 1.367 -12.559 5.002 1.00 1.00 CATOM376 CG ASN A998 2.231 -13.810 4.997 1.00 1.00 CATOM377 OD1 ASN A998 2.670 -14.140 3.905 1.00 1.00 OATOM378 ND2 ASN A998 2.467 -14.470 6.132 1.00 1.00 NATOM379 HA ASN A998 2.616 -11.521 6.386 1.00 1.00 HATOM380 HB1 ASN A998 0.891 -12.436 4.052 1.00 1.00 HATOM381 HB2 ASN A998 0.514 -12.665 5.696 1.00 1.00 HATOM382 HD22 ASN A998 2.897 -15.364 6.112 1.00 1.00 HATOM383 HD21 ASN A998 2.312 -14.069 7.033 1.00 1.00 HATOM384 HN ASN A998 0.313 -10.286 5.719 1.00 1.00 HATOM385 NLEU A999 2.881 -10.391 3.316 1.00 1.00 NATOM386 CA LEU A999 3.856 -9.9882.322 1.00 1.00 CATOM387 CLEU A999 4.903 -9.2013.064 1.00 1.00 CATOM388 OLEU A999 6.060 -9.6013.015 1.00 1.00 OATOM389 CB LEU A999 3.158 -9.2721.177 1.00 1.00 CATOM390 CG LEU A999 4.179 -8.5280.215 1.00 1.00 CATOM391 CD1 LEU A999 4.903 -9.527 -0.718 1.00 1.00 CATOM392 CD2 LEU A999 3.464 -7.520 -0.646 1.00 1.00 CATOM393 HA LEU A999 4.320 -10.935 1.944 1.00 1.00 HATOM394 HB1 LEU A999 2.441 -8.5481.532 1.00 1.00 HATOM395 HB2 LEU A999 2.559 -10.037 0.608 1.00 1.00 HATOM396 HG LEU A999 4.865 -7.9160.821 1.00 1.00 HATOM397 HD21 LEU A999 4.178 -7.005 -1.284 1.00 1.00 HATOM398 HD22 LEU A999 2.997 -6.758 -0.017 1.00 1.00 HATOM399 HD23 LEU A999 2.668 -7.932 -1.257 1.00 1.00 HATOM400 HD11 LEU A999 4.130 -10.167 -1.186 1.00 1.00 HATOM401 HD12 LEU A999 5.538 -10.184 -0.160 1.00 1.00 HATOM402 HD13 LEU A999 5.521 -8.939 -1.445 1.00 1.00 HATOM403 HN LEU A999 1.910 -10.254 3.145 1.00 1.00 HATOM404 NLEU A1000 4.585 -8.0593.731 1.00 1.00 N
ATOM405 CA LEU A1000 5.596 -7.2034.354 1.00 1.00 CATOM406 CLEU A1000 6.383 -7.9805.400 1.00 1.00 CATOM407 OLEU A1000 7.598 -7.9995.425 1.00 1.00 OATOM408 CB LEU A1000 5.062 -5.8715.014 1.00 1.00 CATOM409 CG LEU A1000 4.991 -4.6514.032 1.00 1.00 CATOM410 CD1 LEU A1000 3.821 -4.8423.112 1.00 1.00 CATOM411 CD2 LEU A1000 4.850 -3.3094.826 1.00 1.00 CATOM412 HA LEU A1000 6.291 -6.8693.564 1.00 1.00 HATOM413 HB1 LEU A1000 5.764 -5.5485.752 1.00 1.00 HATOM414 HB2 LEU A1000 4.085 -6.0455.513 1.00 1.00 HATOM415 HG LEU A1000 5.902 -4.6753.478 1.00 1.00 HATOM416 HD21 LEU A1000 5.685 -3.1365.555 1.00 1.00 HATOM417 HD22 LEU A1000 3.875 -3.1975.322 1.00 1.00 HATOM418 HD23 LEU A1000 4.969 -2.5504.059 1.00 1.00 HATOM419 HD11 LEU A1000 3.817 -3.9552.444 1.00 1.00 HATOM420 HD12 LEU A1000 2.860 -4.8433.696 1.00 1.00 HATOM421 HD13 LEU A1000 3.881 -5.7282.498 1.00 1.00 HATOM422 HN LEU A1000 3.624 -7.7983.854 1.00 1.00 HATOM423 NGLU A1001 5.657 -8.4756.433 1.00 1.00 NATOM424 CA GLU A1001 6.268 -9.0687.581 1.00 1.00 CATOM425 CGLU A1001 6.909 -10.414 7.205 1.00 1.00 CATOM426 OGLU A1001 8.065 -10.623 7.537 1.00 1.00 OATOM427 CB GLU A1001 5.333 -9.2538.748 1.00 1.00 CATOM428 CG GLU A1001 4.709 -7.9289.242 1.00 1.00 CATOM429 CD GLU A1001 5.624 -6.8539.748 1.00 1.00 CATOM430 OE1 GLU A1001 5.510 -5.6159.530 1.00 1.00 OATOM431 OE2 GLU A1001 6.579 -7.19110.502 1.00 1.00 OATOM432 HA GLU A1001 7.154 -8.4747.896 1.00 1.00 HATOM433 HB1 GLU A1001 5.768 -9.7149.702 1.00 1.00 HATOM434 HB2 GLU A1001 4.420 -9.8458.450 1.00 1.00 HATOM435 HG1 GLU A1001 4.044 -8.15210.121 1.00 1.00 HATOM436 HG2 GLU A1001 4.147 -7.4078.451 1.00 1.00 HATOM437 HN GLU A1001 4.675 -8.5416.420 1.00 1.00 HATOM438 NASP A1002 6.228 -11.349 6.578 1.00 1.00 NATOM439 CA ASP A1002 6.803 -12.664 6.307 1.00 1.00 CATOM440 CASP A1002 7.640 -12.784 5.070 1.00 1.00 CATOM441 OASP A1002 8.690 -13.475 5.131 1.00 1.00 OATOM442 CB ASP A1002 5.790 -13.787 6.372 1.00 1.00 CATOM443 CG ASP A1002 5.207 -13.948 7.743 1.00 1.00 CATOM444 OD1 ASP A1002 4.236 -13.227 8.054 1.00 1.00 OATOM445 OD2 ASP A1002 5.770 -14.768 8.508 1.00 1.00 OATOM446 HA ASP A1002 7.461 -12.913 7.107 1.00 1.00 HATOM447 HB1 ASP A1002 6.336 -14.701 6.059 1.00 1.00 HATOM448 HB2 ASP A1002 4.982 -13.617 5.641 1.00 1.00 HATOM449 HN ASP A1002 5.301 -11.170 6.191 1.00 1.00 HATOM450 NTRP A1003 7.309 -12.155 3.916 1.00 1.00 NATOM451 CA TRP A1003 8.028 -12.521 2.712 1.00 1.00 CATOM452 CTRP A1003 9.347 -11.717 2.607 1.00 1.00 CATOM453 OTRP A1003 10.188 -12.008 1.776 1.00 1.00 OATOM454 CB TRP A1003 7.245 -12.350 1.425 1.00 1.00 CATOM455 CG TRP A1003 5.928 -13.105 1.426 1.00 1.00 CATOM456 CD1 TRP A1003 5.234 -13.742 2.370 1.00 1.00 C
ATOM457 CD2 TRP A1003 5.081-13.269 0.214 1.00 1.00 CATOM458 NE1 TRP A1003 4.125-14.238 1.928 1.00 1.00 NATOM459 CE2 TRP A1003 3.974-13.995 0.622 1.00 1.00 CATOM460 CE3 TRP A1003 5.245-12.863 -1.108 1.00 1.00 CATOM461 CZ2 TRP A1003 2.896-14.356 -0.205 1.00 1.00 CATOM462 CZ3 TRP A1003 4.207-13.291 -1.962 1.00 1.00 CATOM463 CH2 TRP A1003 3.067-13.986 -1.528 1.00 1.00 CATOM464 HA TRP A1003 8.356-13.571 2.796 1.00 1.00 HATOM465 H31 TRP A1003 7.953-12.648 0.620 1.00 1.00 HATOM466 HB2 TRP A1003 7.032-11.308 1.373 1.00 1.00 HATOM467 HE1 TRP A1003 3.372-14.672 2.522 1.00 1.00 HATOM468 HD1 TRP A1003 5.553-13.819 3.437 1.00 1.00 HATOM469 HZ2 TRP A1003 2.034-14.863 0.176 1.00 1.00 HATOM470 HH2 TRP A1003 2.311-14.188 -2.323 1.00 1.00 HATOM471 HZ3 TRP A1003 4.220-13.039 -3.034 1.00 1.00 HATOM472 HE3 TRP A1003 6.091-12.270 -1.397 1.00 1.00 HATOM473 HN TRP A1003 6.524-11.504 3.913 1.00 1.00 HATOM474 N GLY A1004 9.574-10.669 3.477 1.00 1.00 NATOM475 CA GLY A1004 10.789 -9.8953.350 1.00 1.00 CATOM476 C GLY A1004 12.070 -10.653 2.944 1.00 1.00 CATOM477 O GLY A1004 12.762 -10.229 2.015 1.00 1.00 OATOM478 HA2 GLY A1004 11.108 -9.5894.337 1.00 1.00 HATOM479 HA1 GLY A1004 10.654 -9.0482.670 1.00 1.00 HATOM480 HN GLY A1004 8.925-10.435 4.206 1.00 1.00 HATOM481 N PRO A1005 12.579 -11.765 3.541 1.00 1.00 NATOM482 CA PRO A1005 13.852 -12.345 3.150 1.00 1.00 CATOM483 C PRO A1005 13.998 -12.666 1.707 1.00 1.00 CATOM484 O PRO A1005 15.042 -12.420 1.155 1.00 1.00 OATOM485 CB PRO A1005 13.861 -13.680 3.989 1.00 1.00 CATOM486 CG PRO A1005 12.906 -13.370 5.191 1.00 1.00 CATOM487 CD PRO A1005 11.799 -12.434 4.617 1.00 1.00 CATOM488 HA PRO A1005 14.610 -11.606 3.479 1.00 1.00 HATOM489 HD2 PRO A1005 11.403 -11.683 5.350 1.00 1.00 HATOM490 HD1 PRO A1005 10.996 -13.058 4.147 1.00 1.00 HATOM491 HG2 PRO A1005 13.524 -12.917 5.947 1.00 1.00 HATOM492 HG1 PRO A1005 12.483 -14.261 5.628 1.00 1.00 HATOM493 HB1 PRO A1005 14.879 -13.938 4.352 1.00 1.00 HATOM494 HB2 PRO A1005 13.430 -14.571 3.445 1.00 1.00 HATOM495 N CYS A1006 13.035 -13.296 1.074 1.00 1.00 NATOM496 CA CYS A1006 13.140 -13.592 -0.390 1.00 1.00 CATOM497 C CYS A1006 12.762 -12.375 -1.245 1.00 1.00 CATOM498 O CYS A1006 13.351 -12.102 -2.280 1.00 1.00 OATOM499 CB CYS A1006 12.201 -14.795 -0.743 1.00 1.00 CATOM500 SG CYS A1006 12.536 -15.488 -2.352 1.00 1.00 SATOM501 HA CYS A1006 14.177 -13.862 -0.671 1.00 1.00 HATOM502 HB1 CYS A1006 11.120 -14.461 -0.654 1.00 1.00 HATOM503 HB2 CYS A1006 12.290 -15.623 -0.005 1.00 1.00 HATOM504 HG CYS A1006 12.338 -14.714 -2.962 1.00 1.00 HATOM505 HN CYS A1006 12.202 -13.577 1.509 1.00 1.00 HATOM506 N ALA A1007 11.768 -11.607 -0.809 1.00 1.00 NATOM507 CA ALA A1007 11.279 -10.496 -1.619 1.00 1.00 CATOM508 C ALA A1007 12.309 -9.452 -1.823 1.00 1.00 C
ATOM509 O ALA A1007 12.480 -9.009 -2.932 1.00 1.00 OATOM510 CB ALA A1007 9.999 -9.818 -1.009 1.00 1.00 CATOM511 HA ALA A1007 11.063 -10.943 -2.589 1.00 1.00 HATOM512 HB1 ALA A1007 9.218 -10.616 -0.823 1.00 1.00 HATOM513 HB2 ALA A1007 9.534 -9.139 -1.712 1.00 1.00 HATOM514 HB3 ALA A1007 10.199 -9.277 -0.051 1.00 1.00 HATOM515 HN ALA A1007 11.257 -11.726 0.080 1.00 1.00 HATOM516 N GLU A1008 13.008 -9.091 -0.725 1.00 1.00 NATOM517 CA GLU A1008 13.693 -7.774 -0.696 1.00 1.00 CATOM518 C GLU A1008 14.665 -7.6910.450 1.00 1.00 CATOM519 O GLU A1008 15.831 -7.7230.199 1.00 1.00 OATOM520 CB GLU A1008 12.634 -6.641 -0.630 1.00 1.00 CATOM521 CG GLU A1008 13.185 -5.193 -0.873 1.00 1.00 CATOM522 CD GLU A1008 12.086 -4.246 -1.424 1.00 1.00 CATOM523 OE1 GLU A1008 12.389 -3.101 -1.843 1.00 1.00 OATOM524 OE2 GLU A1008 10.882 -4.552 -1.441 1.00 1.00 OATOM525 HA GLU A1008 14.197 -7.740 -1.668 1.00 1.00 HATOM526 HB1 GLU A1008 12.101 -6.6300.347 1.00 1.00 HATOM527 HB2 GLU A1008 11.851 -6.902 -1.395 1.00 1.00 HATOM528 HG1 GLU A1008 13.975 -5.220 -1.627 1.00 1.00 HATOM529 HG2 GLU A1008 13.598 -4.7070.027 1.00 1.00 HATOM530 HN GLU A1008 12.900 -9.5110.168 1.00 1.00 HATOM531 N HIS A1009 14.191 -7.7021.721 1.00 1.00 NATOM532 CA HIS A1009 15.129 -7.8342.854 1.00 1.00 CATOM533 C HIS A1009 14.531 -8.5134.111 1.00 1.00 CATOM534 0 HIS A1009 13.334 -8.3554.185 1.00 1.00 OATOM535 CB HIS A1009 15.698 -6.4603.242 1.00 1.00 CATOM536 CG HIS A1009 16.848 -6.5534.172 1.00 1.00 CATOM537 ND1 HIS A1009 17.993 -7.0993.790 1.00 1.00 NATOM538 CD2 HIS A1009 16.866 -6.1235.466 1.00 1.00 CATOM539 CE1 HIS A1009 18.802 -6.9814.779 1.00 1.00 CATOM540 NE2 HIS A1009 18.240 -6.4205.737 1.00 1.00 NATOM541 HA HIS A1009 15.965 -8.4372.557 1.00 1.00 HATOM542 HB1 HIS A1009 14.890 -5.8453.691 1.00 1.00 HATOM543 HB2 HIS A1009 15.993 -5.9332.353 1.00 1.00 HATOM544 HD2 HIS A1009 16.119 -5.6226.058 1.00 1.00 HATOM545 HE1 HIS A1009 19.819 -7.3104.776 1.00 1.00 HATOM546 HD1 HIS A1009 18.137 -7.5202.864 1.00 1.00 HATOM547 HN HIS A1009 13.219 -7.7381.935 1.00 1.00 HATOM548 N GLY A1010 15.273 -9.2565.002 1.00 1.00 NATOM549 CA GLY A1010 14.575 -10.077 5.994 1.00 1.00 CATOM550 C GLY A1010 14.714 -9.6437.436 1.00 1.00 CATOM551 O GLY A1010 15.653 -10.008 8.103 1.00 1.00 OATOM552 HA2 GLY A1010 14.989 -11.128 5.893 1.00 1.00 HATOM553 HA1 GLY A1010 13.490 -10.283 5.842 1.00 1.00 HATOM554 HN GLY A1010 16.306 -9.1875.018 1.00 1.00 HATOM555 N GLU A1011 13.728 -8.8547.989 1.00 1.00 NATOM556 CA GLU A1011 13.576 -8.6149.409 1.00 1.00 CATOM557 C GLU A1011 12.120 -8.3829.661 1.00 1.00 CATOM558 O GLU A1011 11.447 -7.9238.762 1.00 1.00 OATOM559 CB GLU A1011 14.497 -7.54110.090 1.00 1.00 CATOM560 CG GLU A1011 15.881 -7.3389.382 1.00 1.00 C
ATOM561 CD GLU A1011 16.599 -6.107 9.925 1.00 1.00 CATOM562 OE1 GLU A1011 17.092 -6.200 11.097 1.00 1.00 OATOM563 OE2 GLU A1011 16.641 -5.074 9.204 1.00 1.00 OATOM564 HA GLU A1011 13.813 -9.563 9.869 1.00 1.00 HATOM565 HB1 GLU A1011 14.790 -7.854 11.113 1.00 1.00 HATOM566 HB2 GLU A1011 13.951 -6.587 10.133 1.00 1.00 HATOM567 HG1 GLU A1011 15.735 -7.095 8.320 1.00 1.00 HATOM568 HG2 GLU A1011 16.514 -8.204 9.420 1.00 1.00 HATOM569 HN GLU A1011 13.020 -8.452 7.393 1.00 1.00 HATOM570 N HIS A1012 11.609 -8.618 10.854 1.00 1.00 NATOM571 CA HIS A1012 10.281 -8.224 11.285 1.00 1.00 CATOM572 C HIS A1012 10.120 -6.697 11.403 1.00 1.00 CATOM573 O HIS A1012 8.984 -6.206 11.289 1.00 1.00 OATOM574 CB HIS A1012 10.009 -8.931 12.631 1.00 1.00 CATOM575 CG HIS A1012 8.618 -8.870 13.196 1.00 1.00 CATOM576 ND1 HIS A1012 7.532 -8.538 12.505 1.00 1.00 NATOM577 CD2 HIS A1012 8.326 -9.177 14.481 1.00 1.00 CATOM578 CE1 HIS A1012 6.524 -8.651 13.325 1.00 1.00 CATOM579 NE2 HIS A1012 6.902 -9.013 14.449 1.00 1.00 NATOM580 HA HIS A1012 9.522 -8.610 10.525 1.00 1.00 HATOM581 HB1 HIS A1012 10.152 -9.977 12.534 1.00 1.00 HATOM582 HB2 HIS A1012 10.717 -8.555 13.418 1.00 1.00 HATOM583 HD2 HIS A1012 8.909 -9.453 15.354 1.00 1.00 HATOM584 HE1 HIS A1012 5.463 -8.501 13.067 1.00 1.00 HATOM585 HD1 HIS A1012 7.408 -8.258 11.514 1.00 1.00 HATOM586 HN HIS A1012 12.300 -8.840 11.572 1.00 1.00 HATOM587 N HIS A1013 11.232 -6.029 11.736 1.00 1.00 NATOM588 CA HIS A1013 11.110 -4.544 11.780 1.00 1.00 CATOM589 C HIS A1013 12.444 -4.134 11.211 1.00 1.00 CATOM590 O HIS A1013 13.406 -4.740 11.670 1.00 1.00 OATOM591 CB HIS A1013 10.910 -4.048 13.266 1.00 1.00 CATOM592 CG HIS A1013 9.477 -4.364 13.626 1.00 1.00 CATOM593 ND1 HIS A1013 9.121 -5.479 14.204 1.00 1.00 NATOM594 CD2 HIS A1013 8.373 -3.633 13.366 1.00 1.00 CATOM595 CE1 HIS A1013 7.838 -5.535 14.325 1.00 1.00 CATOM596 NE2 HIS A1013 7.328 -4.511 13.833 1.00 1.00 NATOM597 HA HIS A1013 10.262 -4.131 11.199 1.00 1.00 HATOM598 HB1 HIS A1013 11.679 -4.363 13.999 1.00 1.00 HATOM599 HB2 HIS A1013 10.996 -2.960 13.308 1.00 1.00 HATOM600 HD2 HIS A1013 8.193 -2.661 12.879 1.00 1.00 HATOM601 HE1 HIS A1013 7.261 -6.389 14.794 1.00 1.00 HATOM602 HD1 HIS A1013 9.771 -6.235 14.500 1.00 1.00 HATOM603 HN HIS A1013 12.195 -6.340 11.887 1.00 1.00 HATOM604 N ILE A1014 12.590 -3.234 10.211 1.00 1.00 NATOM605 CA ILE A1014 13.685 -3.372 9.255 1.00 1.00 CATOM606 C ILE A1014 14.754 -2.275 9.212 1.00 1.00 CATOM607 O ILE A1014 14.499 -1.144 9.624 1.00 1.00 OATOM608 CB ILE A1014 13.171 -3.729 7.812 1.00 1.00 CATOM609 CG1 ILE A1014 12.885 -5.239 7.605 1.00 1.00 CATOM610 CG2 ILE A1014 13.960 -3.076 6.642 1.00 1.00 CATOM611 CD1 ILE A1014 12.325 -5.628 6.248 1.00 1.00 CATOM612 HA ILE A1014 14.282 -4.190 9.625 1.00 1.00 H
ATOM 613 HBILE A1014 12.184 -3.275 7.657 1.00 1.00 HATOM 614 HG11 ILE A1014 12.319 -5.577 8.539 1.00 1.00 HATOM 615 HG121 ILE A1014 13.857 -5.787 7.696 1.00 1.00 HATOM 616 HD11 ILE A1014 11.944 -6.666 6.346 1.00 1.00 HATOM 617 HD121 ILE A1014 13.091 -5.524 5.442 1.00 1.00 HATOM 618 HD13 ILE A1014 11.464 -4.987 6.026 1.00 1.00 HATOM 619 HG21 ILE A1014 14.091 -1.994 6.867 1.00 1.00 HATOM 620 HG22 ILE A1014 13.499 -3.189 5.668 1.00 1.00 HATOM 621 HG23 ILE A1014 14.973 -3.496 6.609 1.00 1.00 HATOM 622 HNILE A1014 11.903 -2.580 10.056 1.00 1.00 HATOM 623 N ARG A1015 16.014 -2.546 8.737 1.00 1.00 NATOM 624 CAARG A1015 16.987 -1.486 8.662 1.00 1.00 CATOM 625 C ARG A1015 17.689 -1.508 7.323 1.00 1.00 CATOM 626 O ARG A1015 18.822 -1.972 7.278 1.00 1.00 OATOM 627 CBARG A1015 18.007 -1.842 9.771 1.00 1.00 CATOM 628 CGARG A1015 17.456 -1.744 11.238 1.00 1.00 CATOM 629 CDARG A1015 18.060 -2.774 12.261 1.00 1.00 CATOM 630 NEARG A1015 17.231 -3.975 12.319 1.00 1.00 NATOM 631 CZARG A1015 16.013 -4.069 12.839 1.00 1.00 CATOM 632 NH1 ARG A1015 15.292 -3.038 13.241 1.00 1.00 NATOM 633 NH2 ARG A1015 15.510 -5.259 12.831 1.00 1.00 NATOM 634 HAARG A1015 16.611 -0.502 8.947 1.00 1.00 HATOM 635 HB1 ARG A1015 18.912 -1.220 9.712 1.00 1.00 HATOM 636 HB2 ARG A1015 18.351 -2.906 9.577 1.00 1.00 HATOM 637 HG1 ARG A1015 16.383 -1.931 11.217 1.00 1.00 HATOM 638 HG2 ARG A1015 17.609 -0.732 11.589 1.00 1.00 HATOM 639 HD1 ARG A1015 18.248 -2.319 13.240 1.00 1.00 HATOM 640 HD2 ARG A1015 19.070 -2.990 11.924 1.00 1.00 HATOM 641 HEARG A1015 17.649 -4.860 11.908 1.00 1.00 HATOM 642 HH12 ARG A1015 14.286 -3.178 13.481 1.00 1.00 HATOM 643 HH11 ARG A1015 15.708 -2.115 13.328 1.00 1.00 HATOM 644 HH22 ARG A1015 14.536 -5.398 13.096 1.00 1.00 HATOM 645 HH21 ARG A1015 16.022 -6.088 12.521 1.00 1.00 HATOM 646 HNARG A1015 16.256 -3.478 8.436 1.00 1.00 HATOM 647 N ILE A1016 17.112 -1.036 6.187 1.00 1.00 NATOM 648 CAILE A1016 17.744 -1.151 4.861 1.00 1.00 CATOM 649 C ILE A1016 17.828 0.143 4.154 1.00 1.00 CATOM 650 O ILE A1016 17.215 0.456 3.143 1.00 1.00 OATOM 651 CBILE A1016 16.852 -2.211 4.113 1.00 1.00 CATOM 652 CG1 ILE A1016 17.464 -2.750 2.756 1.00 1.00 CATOM 653 CG2 ILE A1016 15.409 -1.771 3.753 1.00 1.00 CATOM 654 CD1 ILE A1016 18.833 -3.425 2.918 1.00 1.00 CATOM 655 HAILE A1016 18.749 -1.526 4.976 1.00 1.00 HATOM 656 HBILE A1016 16.805 -3.106 4.737 1.00 1.00 HATOM 657 HG11 ILE A1016 17.570 -1.916 2.057 1.00 1.00 HATOM 658 HG12 ILE A1016 16.741 -3.458 2.341 1.00 1.00 HATOM 659 HD11 ILE A1016 19.274 -3.738 1.934 1.00 1.00 HATOM 660 HD12 ILE A1016 18.735 -4.359 3.455 1.00 1.00 HATOM 661 HD13 ILE A1016 19.573 -2.864 3.460 1.00 1.00 HATOM 662 HG21 ILE A1016 15.394 -1.127 2.833 1.00 1.00 HATOM 663 HG22 ILE A1016 14.863 -1.247 4.557 1.00 1.00 HATOM 664 HG23 ILE A1016 14.802 -2.654 3.541 1.00 1.00 H
ATOM665 HN ILE A1016 16.227 -0.604 6.290 1.00 1.00 HATOM666 NPRO A1017 18.621 1.174 4.671 1.00 1.00 NATOM667 CA PRO A1017 19.242 1.116 5.940 1.00 1.00 CATOM668 CPRO A1017 18.335 1.725 6.950 1.00 1.00 CATOM669 OPRO A1017 17.226 1.983 6.608 1.00 1.00 OATOM670 CB PRO A1017 20.375 2.093 5.695 1.00 1.00 CATOM671 CG PRO A1017 19.695 3.181 4.807 1.00 1.00 CATOM672 CD PRO A1017 18.792 2.397 3.813 1.00 1.00 CATOM673 HA PRO A1017 19.600 0.156 6.335 1.00 1.00 HATOM674 HD2 PRO A1017 19.329 2.199 2.845 1.00 1.00 HATOM675 HD1 PRO A1017 17.866 2.928 3.603 1.00 1.00 HATOM676 HG2 PRO A1017 20.511 3.776 4.321 1.00 1.00 HATOM677 HG1 PRO A1017 19.030 3.841 5.449 1.00 1.00 HATOM678 HB1 PRO A1017 21.116 1.507 5.158 1.00 1.00 HATOM679 HB2 PRO A1017 20.922 2.417 6.574 1.00 1.00 HATOM680 NARG A1018 18.779 1.992 8.207 1.00 1.00 NATOM681 CA ARG A1018 17.909 2.706 9.182 1.00 1.00 CATOM682 CARG A1018 17.542 4.047 8.616 1.00 1.00 CATOM683 OARG A1018 18.478 4.541 8.05.9 1.00 1.00 OATOM684 CB ARG A1018 18.426 2.791 10.673 1.00 1.00 CATOM685 CG ARG A1018 19.402 4.036 10.992 1.00 1.00 CATOM686 CD ARG A1018 20.739 4.014 10.143 1.00 1.00 CATOM687 NE ARG A1018 21.410 5.301 10.349 1.00 1.00 NATOM688 CZ ARG A1018 21.016 6.405 9.756 1.00 1.00 CATOM689 NH1 ARG A1018 20.049 6.477 8.903 1.00 1.00 NATOM690 NH2 ARG A1018 21.604 7.529 10.073 1.00 1.00 NATOM691 HA ARG A1018 17.009 2.059 9.180 1.00 1.00 HATOM692 HB1 ARG A1018 18.926 1.763 10.841 1.00 1.00 HATOM693 HB2 ARG A1018 17.567 2.860 11.362 1.00 1.00 HATOM694 HG1 ARG A1018 19.608 3.965 12.092 1.00 1.00 HATOM695 HG2 ARG A1018 18.800 4.907 10.742 1.00 1.00 HATOM696 HD1 ARG A1018 20.683 3.797 9.046 1.00 1.00 HATOM697 HD2 ARG A1018 21.308 3.163 10.562 1.00 1.00 HATOM698 HE ARG A1018 22.227 5.305 11.015 1.00 1.00 HATOM699 HH12 ARG A1018 19.677 7.409 8.592 1.00 1.00 HATOM700 HH11 ARG A1018 19.563 5.660 8.503 1.00 1.00 HATOM701 HH22 ARG A1018 21.435 8.443 9.626 1.00 1.00 HATOM702 HH21 ARG A1018 22.377 7.548 10.756 1.00 1.00 HATOM703 HN ARG A1018 19.689 1.690 8.504 1.00 1.00 HATOM704 NTHR A1019 16.342 4.646 8.771 1.00 1.00 NATOM705 CA THR A1019 15.963 5.870 8.099 1.00 1.00 CATOM706 CTHR A1019 17.119 6.661 7.512 1.00 1.00 CATOM707 OTHR A1019 17.811 7.250 8.338 1.00 1.00 OATOM708 CB THR A1019 15.176 6.800 9.031 1.00 1.00 CATOM709 OG1 THR A1019 14.107 6.049 9.613 1.00 1.00 OATOM710 CG2 THR A1019 14.667 8.092 8.334 1.00 1.00 CATOM711 HA THR A1019 15.280 5.508 7.320 1.00 1.00 HATOM712 HB THR A1019 15.827 7.064 9.924 1.00 1.00 HATOM713 HG1 THR A1019 13.360 5.872 9.049 1.00 1.00 HATOM714 HG23 THR A1019 14.028 8.640 9.037 1.00 1.00 HATOM715 HG21 THR A1019 14.145 7.866 7.430 1.00 1.00 HATOM716 HG22 THRA1019 15.487 8.755 8.092 1.00 1.00 H
ATOM717 HN THR A1019 15.591 4.131 9.265 1.00 1.00HATOM718 NPRO A1020 17.430 6.731 6.176 1.00 1.00NATOM719 CA PRO A1020 18.658 7.406 5.722 1.00 1.00CATOM720 CPRO A1020 18.746 8.864 6.088 1.00 1.00CATOM721 OPRO A1020 19.810 9.296 6.487 1.00 1.00OATOM722 CB PRO A1020 18.650 7.085 4.198 1.00 1.00CATOM723 CG PRO A1020 17.161 6.890 3.860 1.00 1.00CATOM724 CD PRO A1020 16.646 6.138 5.141 1.00 1.00CATOM725 HA PRO A1020 19.511 6.905 6.196 1.00 1.00HATOM726 HD2 PRO A1020 16.893 5.028 5.160 1.00 1.00HATOM727 HD1 PRO A1020 15.618 6.310 5.250 1.00 1.00HATOM728 HG2 PRO A1020 17.012 6.380 2.894 1.00 1.00HATOM729 HG1 PRO A1020 16.726 7.913 3.768 1.00 1.00HATOM730 HB1 PRO A1020 19.107 6.093 4.090 1.00 1.00HATOM731 HB2 PRO A1020 19.185 7.823 3.554 1.00 1.00HATOM732 NALA A1021 17.585 9.577 6.038 1.00 1.00NATOM733 CA ALA A1021 17.602 11.032 6.320 1.00 1.00CATOM734 CALA A1021 16.275 11.586 5.848 1.00 1.00CATOM735 OALA A1021 15.345 10.816 5.679 1.00 1.00OATOM736 CB ALA A1021 17.852 11.440 7.802 1.00 1.00CATOM737 HA ALA A1021 18.337 11.461 5.676 1.00 1.00HATOM738 HB1 ALA A1021 18.764 11.098 8.306 1.00 1.00HATOM739 HB2 ALA A1021 17.875 12.527 7.957 1.00 1.00HATOM740 HB3 ALA A1021 16.963 11.095 8.405 1.00 1.00HATOM741 HN ALA A1021 16.680 9.152 5.787 1.00 1.00HATOM742 NARG A1022 16.120 12.927 5.722 1.00 1.00NATOM743 CA ARG A1022 14.899 13.481 5.135 1.00 1.00CATOM744 CARG A1022 15.022 13.508 3.582 1.00 1.00CATOM745 OARG A1022 15.120 14.546 2.933 1.00 1.00OATOM746 CB ARG A1022 14.518 14.956 5.579 1.00 1.00CATOM747 CG ARG A1022 14.320 15.063 7.122 1.00 1.00CATOM748 CD ARG A1022 13.430 14.008 7.799 1.00 1.00CATOM749 NE ARG A1022 13.016 14.505 9.134 1.00 1.00NATOM750 CZ ARG A1022 11.988 15.295 9.376 1.00 1.00CATOM751 NH1 ARG A1022 11.204 15.758 8.413 1.00 1.00NATOM752 NH2 ARG A1022 11.687 15.636 10.601 1.00 1.00NATOM753 HA ARG A1022 14.045 12.836 5.326 1.00 1.00HATOM754 HB1 ARG A1022 13.518 15.165 5.172 1.00 1.00HATOM755 HB2 ARG A1022 15.204 15.695 5.184 1.00 1.00HATOM756 HG1 ARG A1022 13.996 16.071 7.407 1.00 1.00HATOM757 HG2 ARG A1022 15.288 14.893 7.696 1.00 1.00HATOM758 HD1 ARG A1022 13.931 13.046 7.887 1.00 1.00HATOM759 HD2 ARG A1022 12.565 13.774 7.151 1.00 1.00HATOM760 HE ARG A1022 13.595 14.141 9.934 1.00 1.00HATOM761 HH12 ARG A1022 10.349 16.269 8.666 1.00 1.00HATOM762 HH11 ARG A1022 11.353 15.593 7.413 1.00 1.00HATOM763 HH22 ARG A1022 10.872 16.223 10.882 1.00 1.00HATOM764 HH21 ARG A1022 12.271 15.348 11.396 1.00 1.00HATOM765 HN ARG A1022 16.918 13.574 5.823 1.00 1.00HATOM766 NVAL A1023 15.073 12.283 3.012 1.00 1.00NATOM767 CA VAL A1023 15.273 12.074 1.597 1.00 1.00CATOM768 CVAL A1023 14.378 11.000 1.024 1.00 1.00C
ATOM769 OVAL A1023 14.774 10.330 0.099 1.00 1.00 OATOM770 CB VAL A1023 16.753 11.699 1.206 1.00 1.00 CATOM771 CG1 VAL A1023 17.637 12.969 1.434 1.00 1.00 CATOM772 CG2 VAL A1023 17.181 10.477 2.104 1.00 1.00 CATOM773 HA VAL A1023 14.944 12.951 0.998 1.00 1.00 HATOM774 HB VAL A1023 16.778 11.494 0.137 1.00 1.00 HATOM775 HG11 VAL A1023 18.673 12.806 1.007 1.00 1.00 HATOM776 HG12 VAL A1023 17.701 13.246 2.486 1.00 1.00 HATOM777 HG13 VAL A1023 17.170 13.814 0.863 1.00 1.00 HATOM778 HG21 VAL A1023 17.212 10.724 3.138 1.00 1.00 HATOM779 HG22 VAL A1023 16.430 9.661 2.006 1.00 1.00 HATOM780 HG23 VAL A1023 18.136 10.112 1.690 1.00 1.00 HATOM781 HN VAL A1023 15.004 11.454 3.568 1.00 1.00 HATOM782 NTHR A1024 13.160 10.779 1.573 1.00 1.00 NATOM783 CA THR A1024 12.372 9.608 1.227 1.00 1.00 CATOM784 CTHR A1024 10.935 9.890 0.843 1.00 1.00 CATOM785 OTHR A1024 10.485 11.015 1.023 1.00 1.00 OATOM786 CB THR A1024 12.275 8.696 2.522 1.00 1.00 CATOM787 OG1 THR A1024 11.422 9.231 3.545 1.00 1.00 OATOM788 CG2 THR A1024 13.640 8.367 3.107 1.00 1.00 CATOM789 HA THR A1024 12.814 9.036 0.393 1.00 1.00 HATOM790 HB THR A1024 11.791 7.804 2.224 1.00 1.00 HATOM791 HG1 THR A1024 10.502 9.318 3.394 1.00 1.00 HATOM792 HG23 THR A1024 14.197 7.868 2.298 1.00 1.00 HATOM793 HG21 THR A1024 13.620 7.711 4.033 1.00 1.00 HATOM794 HG22 THR A1024 14.198 9.266 3.335 1.00 1.00 HATOM795 HN THR A1024 12.762 11.411 2.285 1.00 1.00 HATOM796 NGLY A1025 10.185 8.874 0.351 1.00 1.00 NATOM797 CA GLY A1025 8.7348.969 0.398 1.00 1.00 CATOM798 CGLY A1025 8.3268.401 1.707 1.00 1.00 CATOM799 OGLY A1025 9.2328.218 2.517 1.00 1.00 OATOM800 HA2 GLY A1025 8.1668.441 -0.345 1.00 1.00 HATOM801 HA1 GLY A1025 8.3509.977 0.410 1.00 1.00 HATOM802 HN GLY A1025 10.598 7.974 0.035 1.00 1.00 HATOM803 NGLY A1026 7.0088.082 1.999 1.00 1.00 NATOM804 CA GLY A1026 6.7917.393 3.295 1.00 1.00 CATOM805 CGLY A1026 5.4187.637 3.830 1.00 1.00 CATOM806 OGLY A1026 4.8888.695 3.496 1.00 1.00 OATOM807 HA2 GLY A1026 7.4887.734 4.077 1.00 1.00 HATOM808 HA1 GLY A1026 6.9296.286 3.267 1.00 1.00 HATOM809 HN GLY A1026 6.2948.212 1.295 1.00 1.00 HATOM810 NVAL A1027 4.8086.665 4.575 1.00 1.00 NATOM811 CA VAL A1027 3.3466.644 4.858 1.00 1.00 CATOM812 CVAL A1027 2.9995.915 6.098 1.00 1.00 CATOM813 OVAL A1027 3.7095.029 6.544 1.00 1.00 OATOM814 CB VAL A1027 2.6165.960 3.638 1.00 1.00 CATOM815 CG1 VAL A1027 2.6526.832 2.344 1.00 1.00 CATOM816 CG2 VAL A1027 3.0354.473 3.448 1.00 1.00 CATOM817 HA VAL A1027 2.9507.672 5.004 1.00 1.00 HATOM818 HB VAL A1027 1.5645.966 3.870 1.00 1.00 HATOM819 HG11 VAL A1027 2.4447.827 2.695 1.00 1.00 HATOM820 HG12 VAL A1027 3.6396.684 1.874 1.00 1.00 H
ATOM821 HG13 VAL A1027 1.869 6.467 1.624 1.00 1.00 HATOM822 HG21 VAL A1027 2.938 3.815 4.333 1.00 1.00 HATOM823 HG22 VAL A1027 2.391 4.065 2.645 1.00 1.00 HATOM824 HG23 VAL A1027 4.106 4.372 3.104 1.00 1.00 HATOM825 HN VAL A1027 5.273 5.810 4.784 1.00 1.00 HATOM826 NPHE A1028 1.894 6.323 6.764 1.00 1.00 NATOM827 CA PHE A1028 1.539 5.707 8.037 1.00 1.00 CATOM828 CPHE A1028 0.328 4.864 7.801 1.00 1.00 CATOM829 OPHE A1028 -0.753 5.340 8.145 1.00 1.00 OATOM830 CB PHE A1028 1.276 6.894 9.064 1.00 1.00 CATOM831 CG PHE A1028 1.037 6.511 10.563 1.00 1.00 CATOM832 CD1 PHE A1028 2.061 5.823 11.222 1.00 1.00 CATOM833 CD2 PHE A1028 -0.124 6.875 11.317 1.00 1.00 CATOM834 CE1 PHE A1028 2.015 5.498 12.579 1.00 1.00 CATOM835 CE2 PHE A1028 -0.111 6.607 12.703 1.00 1.00 CATOM836 CZ PHE A1028 0.928 5.939 13.328 1.00 1.00 CATOM837 HA PHE A1028 2.444 5.182 8.477 1.00 1.00 HATOM838 HB1 PHE A1028 0.372 7.381 8.624 1.00 1.00 HATOM839 HB2 PHE A1028 2.185 7.529 9.043 1.00 1.00 HATOM840 HD2 PHE A1028 -0.929 7.394 10.815 1.00 1.00 HATOM841 HE2 PHE A1028 -0.997 6.943 13.184 1.00 1.00 HATOM842 HZ PHE A1028 0.926 5.716 14.364 1.00 1.00 HATOM843 HE1 PHE A1028 2.791 4.888 13.051 1.00 1.00 HATOM844 HD1 PHE A1028 2.943 5.531 10.685 1.00 1.00 HATOM845 HN PHE A1028 1.329 7.077 6.348 1.00 1.00 HATOM846 NLEU A1029 0.445 3.661 7.177 1.00 1.00 NATOM847 CA LEU A1029 -0.702 2.765 6.963 1.00 1.00 CATOM848 CLEU A1029 -1.381 2.346 8.273 1.00 1.00 CATOM849 OLEU A1029 -1.312 1.170 8.574 1.00 1.00 OATOM850 CB LEU A1029 -0.449 1.530 6.073 1.00 1.00 CATOM851 CG LEU A1029 0.262 1.770 4.709 1.00 1.00 CATOM852 CD1 LEU A1029 0.664 0.451 3.952 1.00 1.00 CATOM853 CD2 LEU A1029 -0.588 2.712 3.750 1.00 1.00 CATOM854 HA LEU A1029 -1.428 3.398 6.420 1.00 1.00 HATOM855 HB1 LEU A1029 -1.401 1.013 5.841 1.00 1.00 HATOM856 HB2 LEU A1029 0.222 0.889 6.653 1.00 1.00 HATOM857 HG LEU A1029 1.229 2.324 4.865 1.00 1.00 HATOM858 HD21 LEU A1029 -0.643 3.703 4.237 1.00 1.00 HATOM859 HD22 LEU A1029 -0.225 2.784 2.729 1.00 1.00 HATOM860 HD23 LEU A1029 -1.598 2.299 3.653 1.00 1.00 HATOM861 HD11 LEU A1029 -0.162 -0.245 3.883 1.00 1.00 HATOM862 HD12 LEU A1029 1.173 0.568 3.018 1.00 1.00 HATOM863 HD13 LEU A1029 1.338 -0.090 4.611 1.00 1.00 HATOM864 HN LEU A1029 1.352 3.346 6.923 1.00 1.00 HATOM865 NVAL A1030 -2.036 3.276 9.017 1.00 1.00 NATOM866 CA VAL A1030 -2.514 2.944 10.363 1.00 1.00 CATOM867 CVAL A1030 -3.928 3.493 10.529 1.00 1.00 CATOM868 OVAL A1030 -4.092 4.628 10.930 1.00 1.00 OATOM869 CB VAL A1030 -1.541 3.514 11.483 1.00 1.00 CATOM870 CG1 VAL A1030 -2.162 3.124 12.889 1.00 1.00 CATOM871 CG2 VAL A1030 -0.087 2.979 11.373 1.00 1.00 CATOM872 HA VAL A1030 -2.540 1.855 10.563 1.00 1.00 H
ATOM873 HB VAL A1030 -1.548 4.632 11.413 1.00 1.00 HATOM874 HG11 VAL A1030 -2.219 2.041 12.943 1.00 1.00 HATOM875 HG12 VAL A1030 -1.504 3.425 13.753 1.00 1.00 HATOM876 HG13 VAL A1030 -3.156 3.534 13.088 1.00 1.00 HATOM877 HG21 VAL A1030 -0.039 1.865 11.449 1.00 1.00 HATOM878 HG22 VAL A1030 0.249 3.224 10.390 1.00 1.00 HATOM879 HG23 VAL A1030 0.566 3.487 12.175 1.00 1.00 HATOM880 HN VAL A1030 -2.069 4.237 8.753 1.00 1.00 HATOM881 NASP A1031 -4.998 2.703 10.264 1.00 1.00 NATOM882 CA ASP A1031 -6.323 3.075 10.705 1.00 1.00 CATOM883 CASP A1031 -6.418 2.597 12.147 1.00 1.00 CATOM884 OASP A1031 -6.875 1.501 12.395 1.00 1.00 OATOM885 CB ASP A1031 -7.488 2.651 9.759 1.00 1.00 CATOM886 CG ASP A1031 -8.840 2.958 10.310 1.00 1.00 CATOM887 OD1 ASP A1031 -9.102 4.085 10.803 1.00 1.00 OATOM888 OD2 ASP A1031 -9.828 2.098 10.213 1.00 1.00 OATOM889 HA ASP A1031 -6.432 4.192 10.719 1.00 1.00 HATOM890 HB1 ASP A1031 -7.353 1.578 9.643 1.00 1.00 HATOM891 HB2 ASP A1031 -7.464 3.159 8.758 1.00 1.00 HATOM892 HN ASP A1031 -4.859 1.753 9.898 1.00 1.00 HATOM893 NLYS A1032 -5.862 3.344 13.110 1.00 1.00 NATOM894 CA LYS A1032 -5.706 2.950 14.510 1.00 1.00 CATOM895 CLYS A1032 -4.925 1.647 14.580 1.00 1.00 CATOM896 OLYS A1032 -4.731 1.017 13.557 1.00 1.00 OATOM897 CB LYS A1032 -7.091 2.783 15.277 1.00 1.00 CATOM898 CG LYS A1032 -8.139 3.950 15.213 1.00 1.00 CATOM899 CD LYS A1032 -8.936 4.138 13.871 1.00 1.00 CATOM900 CE LYS A1032 -9.780 2.937 13.357 1.00 1.00 CATOM901 NZ LYS A1032 -10.757 3.340 12.246 1.00 1.00 NATOM902 HA LYS A1032 -5.080 3.744 14.990 1.00 1.00 HATOM903 HB1 LYS A1032 -6.811 2.664 16.340 1.00 1.00 HATOM904 HB2 LYS A1032 -7.618 1.874 14.876 1.00 1.00 HATOM905 HG1 LYS A1032 -8.961 3.749 15.941 1.00 1.00 HATOM906 HG2 LYS A1032 -7.649 4.846 15.626 1.00 1.00 HATOM907 HD1 LYS A1032 -8.175 4.437 13.137 1.00 1.00 HATOM908 HD2 LYS A1032 -9.655 4.947 13.949 1.00 1.00 HATOM909 HE1 LYS A1032 -9.035 2.196 13.035 1.00 1.00 HATOM910 HE2 LYS A1032 -10.376 2.455 14.189 1.00 1.00 HATOM911 HZ1 LYS A1032 -11.791 3.366 12.555 1.00 1.00 HATOM912 HZ2 LYS A1032 -10.523 4.239 11.643 1.00 1.00 HATOM913 HZ3 LYS A1032 -10.702 2.515 11.579 1.00 1.00 HATOM914 HN LYS A1032 -5.520 4.269 12.905 1.00 1.00 HATOM915 NASN A1033 -4.474 1.146 15.742 1.00 1.00 NATOM916 CA ASN A1033 -4.194 -0.297 15.887 1.00 1.00 CATOM917 CASN A1033 -3.293 -0.801 14.799 1.00 1.00 CATOM918 OASN A1033 -3.750 -1.617 14.000 1.00 1.00 OATOM919 CB ASN A1033 -5.670 -0.883 15.792 1.00 1.00 CATOM920 CG ASN A1033 -6.578 -0.353 16.832 1.00 1.00 CATOM921 OD1 ASN A1033 -6.164 0.418 17.676 1.00 1.00 OATOM922 ND2 ASN A1033 -7.878 -0.744 16.760 1.00 1.00 NATOM923 HA ASN A1033 -3.714 -0.569 16.839 1.00 1.00 HATOM924 HB1 ASN A1033 -5.611 -1.978 15.909 1.00 1.00 H
ATOM925 HB2 ASN A1033 -6.092 -0.589 14.786 1.00 1.00 HATOM926 HD22 ASN A1033 -8.577 -0.360 17.383 1.00 1.00 HATOM927 HD21 ASN A1033 -8.205 -1.419 16.074 1.00 1.00 HATOM928 HN ASN A1033 -4.525 1.717 16.563 1.00 1.00 HATOM929 NPRO A1034 -2.009 -0.374 14.637 1.00 1.00 NATOM930 CA PRO A1034 -1.185 -0.979 13.653 1.00 1.00 CATOM931 CPRO A1034 -1.365 -2.449 13.617 1.00 1.00 CATOM932 OPRO A1034 -1.454 -3.054 12.573 1.00 1.00 OATOM933 CB PRO A1034 0.269 -0.630 14.070 1.00 1.00 CATOM934 CG PRO A1034 0.067 0.748 14.701 1.00 1.00 CATOM935 CD PRO A1034 -1.283 0.562 15.468 1.00 1.00 CATOM936 HA PRO A1034 -1.446 -0.588 12.622 1.00 1.00 HATOM937 HD2 PRO A1034 -1.836 1.442 15.716 1.00 1.00 HATOM938 HD1 PRO A1034 -1.096 0.033 16.401 1.00 1.00 HATOM939 HG2 PRO A1034 0.017 1.617 14.013 1.00 1.00 HATOM940 HG1 PRO A1034 0.846 0.962 15.467 1.00 1.00 HATOM941 HB1 PRO A1034 0.580 -1.357 14.802 1.00 1.00 HATOM942 HB2 PRO A1034 0.947 -0.601 13.175 1.00 1.00 HATOM943 NHIE A1035 -1.359 -3.141 14.808 1.00 1.00 NATOM944 CA HIE A1035 -1.317 -4.643 14.797 1.00 1.00 CATOM945 CHIE A1035 -1.640 -5.112 16.190 1.00 1.00 CATOM946 OHIE A1035 -0.673 -5.423 16.834 1.00 1.00 OATOM947 CB HIE A1035 0.039 -5.159 14.265 1.00 1.00 CATOM948 HHIE A1035 -1.281 -2.744 15.686 1.00 1.00 HATOM949 CG HIE A1035 0.354 -6.621 14.446 1.00 1.00 CATOM950 ND1 HIE A1035 1.578 -7.286 14.207 1.00 1.00 NATOM951 CD2 HIE A1035 -0.421 -7.629 14.836 1.00 1.00 CATOM952 HA HIE A1035 -2.089 -4.989 14.115 1.00 1.00 HATOM953 CE1 HIE A1035 1.478 -8.515 14.463 1.00 1.00 CATOM954 NE2 HIE A1035 0.253 -8.771 14.850 1.00 1.00 NATOM955 HB2 HIE A1035 0.855 -4.624 14.759 1.00 1.00 HATOM956 HB1 HIE A1035 0.171 -4.956 13.222 1.00 1.00 HATOM957 HD2 HIE A1035 -1.480 -7.468 15.037 1.00 1.00 HATOM958 HE1 HIE A1035 2.355 -9.189 14.363 1.00 1.00 HATOM959 HE2 HIE A1035 -0.085 -9.690 15.150 1.00 1.00 HATOM960 NASN A1036 -2.910 -5.164 16.691 1.00 1.00 NATOM961 CA ASN A1036 -4.136 -4.875 15.844 1.00 1.00 CATOM962 CASN A1036 -5.263 -4.472 16.807 1.00 1.00 CATOM963 OASN A1036 -4.970 -4.084 17.923 1.00 1.00 OATOM964 CB ASN A1036 -4.482 -6.073 14.903 1.00 1.00 CATOM965 CG ASN A1036 -5.157 -7.102 15.763 1.00 1.00 CATOM966 OD1 ASN A1036 -6.376 -7.257 15.743 1.00 1.00 OATOM967 ND2 ASN A1036 -4.383 -7.913 16.523 1.00 1.00 NATOM968 HA ASN A1036 -3.959 -3.937 15.251 1.00 1.00 HATOM969 HB1 ASN A1036 -5.130 -5.788 14.061 1.00 1.00 HATOM970 HB2 ASN A1036 -3.638 -6.561 14.445 1.00 1.00 HATOM971 HD22 ASN A1036 -4.686 -8.580 17.131 1.00 1.00 HATOM972 HD21 ASN A1036 -3.359 -7.811 16.535 1.00 1.00 HATOM973 HN ASN A1036 -3.071 -5.409 17.685 1.00 1.00 HATOM974 NTHR A1037 -6.594 -4.481 16.470 1.00 1.00 NATOM975 CA THR A1037 -7.700 -4.097 17.389 1.00 1.00 CATOM976 CTHR A1037 -8.906 -3.861 16.522 1.00 1.00 C
ATOM977 OTHP A1037 -8.830 -4.381 15.418 1.00 1.00 OATOM978 CB THR A1037 -8.207 -5.234 18.307 1.00 1.00 CATOM979 OG1 THR A1037 -9.321 -4.854 19.141 1.00 1.00 OATOM980 CG2 THR A1037 -7.094 -6.008 19.023 1.00 1.00 CATOM981 HA THR A1037 -7.503 -3.154 17.938 1.00 1.00 HATOM982 HB THR A1037 -8.637 -5.986 17.627 1.00 1.00 HATOM983 HG1 THR A1037 -9.069 -4.190 19.780 1.00 1.00 HATOM984 HG23 THR A1037 -6.300 -6.368 18.382 1.00 1.00 HATOM985 HG21 THR A1037 -6.691 -5.266 19.751 1.00 1.00 HATOM986 HG22 THR A1037 -7.509 -6.875 19.581 1.00 1.00 HATOM987 HN THR A1037 -6.787 -4.808 15.557 1.00 1.00 HATOM988 NALA A1038 -10.036 -3.185 16.947 1.00 1.00 NATOM989 CA ALA A1038 -11.086 -2.839 15.998 1.00 1.00 CATOM990 CALA A1038 -10.459 -2.406 14.685 1.00 1.00 CATOM991 OALA A1038 -9.377 -1.845 14.612 1.00 1.00 OATOM992 CB ALA A1038 -11.861 -1.612 16.556 1.00 1.00 CATOM993 HA ALA A1038 -11.736 -3.734 15.885 1.00 1.00 HATOM994 HB1 ALA A1038 -12.177 -1.626 17.600 1.00 1.00 HATOM995 HB2 ALA A1038 -11.219 -0.703 16.440 1.00 1.00 HATOM996 HB3 ALA A1038 -12.749 -1.455 15.917 1.00 1.00 HATOM997 HN ALA A1038 -10.095 -2.929 17.911 1.00 1.00 HATOM998 NGLU A1039 -11.224 -2.588 13.565 1.00 1.00 NATOM999 CA GLU A1039 -10.831 -2.038 12.277 1.00 1.00 CATOM1000 CGLU A1039 -9.411 -2.435 11.839 1.00 1.00 CATOM1001 OGLU A1039 -9.227 -3.381 11.052 1.00 1.00 OATOM1002 CB GLU A1039 -11.140 -0.513 12.279 1.00 1.00 CATOM1003 CG GLU A1039 -12.659 -0.175 12.381 1.00 1.00 CATOM1004 CD GLU A1039 -12.885 1.303 12.189 1.00 1.00 CATOM1005 OE1 GLU A1039 -13.310 1.823 11.153 1.00 1.00 OATOM1006 OE2 GLU A1039 -12.543 2.080 13.130 1.00 1.00 OATOM1007 HA GLU A1039 -11.423 -2.499 11.439 1.00 1.00 HATOM1008 HB1 GLU A1039 -10.629 -0.012 13.114 1.00 1.00 HATOM1009 HB2 GLU A1039 -10.771 -0.052 11.363 1.00 1.00 HATOM1010 HG1 GLU A1039 -13.223 -0.735 11.639 1.00 1.00 HATOM1011 HG2 GLU A1039 -13.019 -0.610 13.320 1.00 1.00 HATOM1012 HN GLU A1039 -12.061 -3.035 13.569 1.00 1.00 HATOM1013 NSER A1040 -8.357 -1.708 12.312 1.00 1.00 NATOM1014 CA SER A1040 -6.977 -1.982 11.941 1.00 1.00 CATOM1015 CSER A1040 -6.681 -2.124 10.466 1.00 1.00 CATOM1016 OSER A1040 -5.829 -2.905 10.090 1.00 1.00 OATOM1017 CB SER A1040 -6.419 -3.111 12.810 1.00 1.00 CATOM1018 OG SER A1040 -5.037 -3.364 12.715 1.00 1.00 OATOM1019 HA SER A1040 -6.446 -1.084 12.216 1.00 1.00 HATOM1020 HB1 SER A1040 -6.614 -2.873 13.943 1.00 1.00 HATOM1021 HB2 SER A1040 -6.964 -4.023 12.499 1.00 1.00 HATOM1022 HG SER A1040 -4.445 -2.709 13.147 1.00 1.00 HATOM1023 HN SER A1040 -8.537 -1.063 13.105 1.00 1.00 HATOM1024 NARG A1041 -7.449 -1.317 9.6831.00 1.00 NATOM1025 CA ARG A1041 -7.344 -1.379 8.1971.00 1.00 CATOM1026 CARG A1041 -6.081 -0.713 7.7401.00 1.00 CATOM1027 OARG A1041 -5.4710.037 8.4711.00 1.00 OATOM1028 CB ARG A1041 -8.527 -0.722 7.4901.00 1.00 C
ATOM 1029 CG ARG A1041 -9.942 -1.108 8.029 1.00 1.00 CATOM 1030 CD ARG A1041 -11.066 -0.380 7.217 1.00 1.00 CATOM 1031 NE ARG A1041 -12.403 -0.426 7.806 1.00 1.00 NATOM 1032 CZ ARG A1041 -12.755 0.418 8.744 1.00 1.00 CATOM 1033 NH1 ARG A1041 -11.904 1.343 9.199 1.00 1.00 NATOM 1034 NH2 ARG A1041 -13.937 0.325 9.230 1.00 1.00 NATOM 1035 HA ARG A1041 -7.315 -2.450 7.932 1.00 1.00 HATOM 1036 HB1 ARG A1041 -8.509 -0.934 6.402 1.00 1.00 HATOM 1037 HB2 ARG A1041 -8.4080.409 7.586 1.00 1.00 HATOM 1038 HG1 ARG A1041 -10.051 -2.205 7.988 1.00 1.00 HATOM 1039 HG2 ARG A1041 -10.154 -0.862 9.062 1.00 1.00 HATOM 1040 HD1 ARG A1041 -10.773 0.615 6.893 1.00 1.00 HATOM 1041 HD2 ARG A1041 -11.056 -0.916 6.279 1.00 1.00 HATOM 1042 HE ARG A1041 -13.080 -1.113 7.407 1.00 1.00 HATOM 1043 HH12 ARG A1041 -12.254 2.068 9.852 1.00 1.00 HATOM 1044 HH11 ARG A1041 -10.914 1.440 8.906 1.00 1.00 HATOM 1045 HH22 ARG A1041 -14.263 0.873 10.029 1.00 1.00 HATOM 1046 HH21 ARG A1041 -14.566 -0.421 8.938 1.00 1.00 HATOM 1047 HN ARG A1041 -8.034 -0.634 10.099 1.00 1.00 HATOM 1048 NLEU A1042 -5.644 -0.940 6.496 1.00 1.00 NATOM 1049 CA LEU A1042 -4.437 -0.250 6.004 1.00 1.00 CATOM 1050 CLEU A1042 -4.7720.948 5.114 1.00 1.00 CATOM 1051 OLEU A1042 -4.2451.048 4.016 1.00 1.00 OATOM 1052 CB LEU A1042 -3.450 -1.244 5.274 1.00 1.00 CATOM 1053 CG LEU A1042 -2.920 -2.438 6.131 1.00 1.00 CATOM 1054 CD1 LEU A1042 -2.109 -3.503 5.362 1.00 1.00 CATOM 1055 CD2 LEU A1042 -2.109 -1.928 7.332 1.00 1.00 CATOM 1056 HA LEU A1042 -3.8410.258 6.808 1.00 1.00 HATOM 1057 HB1 LEU A1042 -2.642 -0.709 4.798 1.00 1.00 HATOM 1058 HB2 LEU A1042 -3.974 -1.734 4.410 1.00 1.00 HATOM 1059 HG LEU A1042 -3.819 -2.970 6.512 1.00 1.00 HATOM 1060 HD21 LEU A1042 -1.264 -1.324 6.978 1.00 1.00 HATOM 1061 HD22 LEU A1042 -2.778 -1.402 8.005 1.00 1.00 HATOM 1062 HD23 LEU A1042 -1.653 -2.747 7.930 1.00 1.00 HATOM 1063 HD11 LEU A1042 -1.124 -3.131 5.000 1.00 1.00 HATOM 1064 HD12 LEU A1042 -1.984 -4.386 5.976 1.00 1.00 HATOM 1065 HD13 LEU A1042 -2.701 -3.803 4.456 1.00 1.00 HATOM 1066 HN LEU A1042 -6.182 -1.548 5.926 1.00 1.00 HATOM 1067 NVAL A1043 -5.6221.878 5.608 1.00 1.00 NATOM 1068 CA VAL A1043 -5.9253.100 4.855 1.00 1.00 CATOM 1069 CVAL A1043 -4.6543.832 4.401 1.00 1.00 CATOM 1070 OVAL A1043 -3.6683.689 5.109 1.00 1.00 OATOM 1071 CB VAL A1043 -6.7984.024 5.754 1.00 1.00 CATOM 1072 CG1 VAL A1043 -6.8995.517 5.284 1.00 1.00 CATOM 1073 CG2 VAL A1043 -8.2483.510 5.912 1.00 1.00 CATOM 1074 HA VAL A1043 -6.4282.818 3.926 1.00 1.00 HATOM 1075 HB VAL A1043 -6.2934.023 6.722 1.00 1.00 HATOM 1076 HG11 VAL A1043 -7.5856.222 5.814 1.00 1.00 HATOM 1077 HG12 VAL A1043 -5.9076.013 5.180 1.00 1.00 HATOM 1078 HG13 VAL A1043 -7.3305.470 4.276 1.00 1.00 HATOM 1079 HG21 VAL A1043 -8.1982.473 6.227 1.00 1.00 HATOM 1080 HG22 VAL A1043 -8.9084.087 6.550 1.00 1.00 H
ATOM 1081 HG23 VAL A1043 -8.753 3.5284.917 1.00 1.00 HATOM 1082 HN VAL A1043 -5.960 1.7146.581 1.00 1.00 HATOM 1083 NVAL A1044 -4.728 4.5883.267 1.00 1.00 NATOM 1084 CA VAL A1044 -3.533 5.2772.772 1.00 1.00 CATOM 1085 CVAL A1044 -3.361 6.6623.317 1.00 1.00 CATOM 1086 OVAL A1044 -4.313 7.2723.794 1.00 1.00 OATOM 1087 CB VAL A1044 -3.459 5.2171.194 1.00 1.00 CATOM 1088 CG1 VAL A1044 -3.450 3.7430.684 1.00 1.00 CATOM 1089 CG2 VAL A1044 -4.599 5.9430.449 1.00 1.00 CATOM 1090 HA VAL A1044 -2.667 4.7563.209 1.00 1.00 HATOM 1091 HB VAL A1044 -2.441 5.6410.958 1.00 1.00 HATOM 1092 HG11 VAL A1044 -2.639 3.2431.145 1.00 1.00 HATOM 1093 HG12 VAL A1044 -4.341 3.2020.917 1.00 1.00 HATOM 1094 HG13 VAL A1044 -3.321 3.707 -0.385 1.00 1.00 HATOM 1095 HG21 VAL A1044 -5.592 5.5950.774 1.00 1.00 HATOM 1096 HG22 VAL A1044 -4.560 7.0100.734 1.00 1.00 HATOM 1097 HG23 VAL A1044 -4.492 5.940 -0.650 1.00 1.00 HATOM 1098 HN VAL A1044 -5.572 4.5472.719 1.00 1.00 HATOM 1099 NASP A1045 -2.147 7.2613.179 1.00 1.00 NATOM 1100 CA ASP A1045 -1.771 8.4663.930 1.00 1.00 CATOM 1101 CASP A1045 -0.577 9.1533.248 1.00 1.00 CATOM 1102 OASP A1045 0.118 8.5322.457 1.00 1.00 OATOM 1103 CB ASP A1045 -1.359 8.0875.397 1.00 1.00 CATOM 1104 CG ASP A1045 -0.359 9.0116.002 1.00 1.00 CATOM 1105 OD1 ASP A1045 -0.791 10.160 6.177 1.00 1.00 OATOM 1106 OD2 ASP A1045 0.833 8.6646.245 1.00 1.00 OATOM 1107 HA ASP A1045 -2.611 9.1273.881 1.00 1.00 HATOM 1108 HB1 ASP A1045 -1.007 7.0315.455 1.00 1.00 HATOM 1109 HB2 ASP A1045 -2.337 8.0865.941 1.00 1.00 HATOM 1110 HN ASP A1045 -1.392 6.7832.693 1.00 1.00 HATOM 1111 NPHE A1046 -0.285 10.477 3.475 1.00 1.00 NATOM 1112 CA PHE A1046 0.702 11.240 2.701 1.00 1.00 CATOM 1113 CPHE A1046 1.779 11.679 3.708 1.00 1.00 CATOM 1114 OPHE A1046 2.402 12.695 3.395 1.00 1.00 OATOM 1115 CB PHE A1046 0.015 12.428 1.940 1.00 1.00 CATOM 1116 CG PHE A1046 -0.522 13.524 2.908 1.00 1.00 CATOM 1117 CD1 PHE A1046 0.278 14.639 3.196 1.00 1.00 CATOM 1118 CD2 PHE A1046 -1.858 13.517 3.415 1.00 1.00 CATOM 1119 CE1 PHE A1046 -0.266 15.704 3.875 1.00 1.00 CATOM 1120 CE2 PHE A1046 -2.295 14.490 4.293 1.00 1.00 CATOM 1121 CZ PHE A1046 -1.488 15.585 4.510 1.00 1.00 CATOM 1122 HA PHE A1046 1.236 10.624 1.971 1.00 1.00 HATOM 1123 HB1 PHE A1046 -0.849 12.006 1.374 1.00 1.00 HATOM 1124 HB2 PHE A1046 0.709 12.757 1.175 1.00 1.00 HATOM 1125 HD2 PHE A1046 -2.543 12.760 3.092 1.00 1.00 HATOM 1126 HE2 PHE A1046 -3.268 14.364 4.698 1.00 1.00 HATOM 1127 HZ PHE A1046 -1.752 16.372 5.182 1.00 1.00 HATOM 1128 HE1 PHE A1046 0.212 16.635 3.901 1.00 1.00 HATOM 1129 HD1 PHE A1046 1.293 14.720 2.845 1.00 1.00 HATOM 1130 HN PHE A1046 -0.722 10.950 4.239 1.00 1.00 HATOM 1131 NSER A1047 2.025 10.996 4.826 1.00 1.00 NATOM 1132 CA SER A1047 3.022 11.568 5.779 1.00 1.00 C
ATOM 1133 CSER A1047 4.40211.289 5.276 1.00 1.00 CATOM 1134 OSER A1047 5.11210.463 5.855 1.00 1.00 OATOM 1135 CB SER A1047 2.82511.065 7.224 1.00 1.00 CATOM 1136 OG SER A1047 2.9949.6397.422 1.00 1.00 OATOM 1137 HA SER A1047 2.97212.680 5.777 1.00 1.00 HATOM 1138 HB1 SER A1047 1.83111.312 7.609 1.00 1.00 HATOM 1139 HB2 SER A1047 3.53911.572 7.866 1.00 1.00 HATOM 1140 HG SER A1047 2.3229.0697.012 1.00 1.00 HATOM 1141 HN SER A1047 1.60510.091 4.965 1.00 1.00 HATOM 1142 NGLN A1048 4.89811.972 4.199 1.00 1.00 NATOM 1143 CA GLN A1048 6.25311.656 3.667 1.00 1.00 CATOM 1144 CGLN A1048 7.30712.423 4.446 1.00 1.00 CATOM 1145 OGLN A1048 8.03913.250 3.878 1.00 1.00 OATOM 1146 CB GLN A1048 6.39111.985 2.163 1.00 1.00 CATOM 1147 CG GLN A1048 5.33811.340 1.266 1.00 1.00 CATOM 1148 CD GLN A1048 5.69611.402 -0.239 1.00 1.00 CATOM 1149 OE1 GLN A1048 6.25010.404 -0.712 1.00 1.00 OATOM 1150 NE2 GLN A1048 5.53012.540 -0.923 1.00 1.00 NATOM 1151 HA GLN A1048 6.45510.566 3.762 1.00 1.00 HATOM 1152 HB1 GLN A1048 7.42711.638 1.936 1.00 1.00 HATOM 1153 HB2 GLN A1048 6.35613.056 1.891 1.00 1.00 HATOM 1154 HG1 GLN A1048 5.13910.288 1.534 1.00 1.00 HATOM 1155 HG2 GLN A1048 4.37311.860 1.444 1.00 1.00 HATOM 1156 HE22 GLN A1048 5.75412.520 -1.892 1.00 1.00 HATOM 1157 HE21 GLN A1048 5.06213.299 -0.492 1.00 1.00 HATOM 1158 HN GLN A1048 4.32212.678 3.757 1.00 1.00 HATOM 1159 NPHE A1049 7.44812.195 5.760 1.00 1.00 NATOM 1160 CA PHE A1049 8.49812.912 6.571 1.00 1.00 CATOM 1161 CPHE A1049 8.60114.403 6.232 1.00 1.00 CATOM 1162 OPHE A1049 7.66515.130 6.512 1.00 1.00 OATOM 1163 CB PHE A1049 9.80112.078 6.511 1.00 1.00 CATOM 1164 CG PHE A1049 9.47310.773 7.198 1.00 1.00 CATOM 1165 CD1 PHE A1049 9.85410.496 8.519 1.00 1.00 CATOM 1166 CD2 PHE A1049 8.9029.6946.495 1.00 1.00 CATOM 1167 CE1 PHE A1049 9.6269.2859.188 1.00 1.00 CATOM 1168 CE2 PHE A1049 8.4828.5427.201 1.00 1.00 CATOM 1169 CZ PHE A1049 8.8118.3588.545 1.00 1.00 CATOM 1170 HA PHE A1049 8.19812.971 7.638 1.00 1.00 HATOM 1171 HB1 PHE A1049 10.563 12.551 7.155 1.00 1.00 HATOM 1172 HB2 PHE A1049 10.132 11.975 5.445 1.00 1.00 HATOM 1173 HD2 PHE A1049 8.7389.6385.419 1.00 1.00 HATOM 1174 HE2 PHE A1049 7.9417.7986.654 1.00 1.00 HATOM 1175 HZ PHE A1049 8.4327.5229.132 1.00 1.00 HATOM 1176 HE1 PHE A1049 10.105 9.03410.133 1.00 1.00 HATOM 1177 HD1 PHE A1049 10.439 11.238 9.063 1.00 1.00 HATOM 1178 HN PHE A1049 6.83811.539 6.215 1.00 1.00 HATOM 1179 NSER A1050 9.67714.898 5.553 1.00 1.00 NATOM 1180 CA SER A1050 9.65716.301 5.183 1.00 1.00 CATOM 1181 CSER A1050 8.80616.291 3.968 1.00 1.00 CATOM 1182 OSER A1050 9.24816.495 2.835 1.00 1.00 OATOM 1183 CB SER A1050 11.091 16.966 4.968 1.00 1.00 CATOM 1184 OG SER A1050 11.822 17.056 6.204 1.00 1.00 O
ATOM 1185 HA SER A10509.134 16.968 5.888 1.00 1.00 HATOM 1186 HB1 SER A105011.585 16.339 4.248 1.00 1.00 HATOM 1187 HB2 SER A105011.028 18.029 4.549 1.00 1.00 HATOM 1188 HG SER A105111.416 17.706 6.822 1.00 1.00 HATOM 1189 HN SER A105110.417 14.348 5.200 1.00 1.00 HATOM 1190 NARG A10517.504 16.069 4.104 1.00 1.00 NATOM 1191 CA ARG A10516.512 16.140 3.037 1.00 1.00 CATOM 1192 CARG A10516.472 17.509 2.374 1.00 1.00 CATOM 1193 OARG A10516.785 18.476 3.011 1.00 1.00 OATOM 1194 CB ARG A10515.120 15.778 3.598 1.00 1.00 CATOM 1195 CG ARG A10514.306 16.806 4.460 1.00 1.00 CATOM 1196 CD ARG A10514.940 17.278 5.811 1.00 1.00 CATOM 1197 NE ARG A10516.076 18.199 5.698 1.00 1.00 NATOM 1198 CZ ARG A10516.823 18.520 6.683 1.00 1.00 CATOM 1199 NH1 ARG A10516.585 18.076 7.890 1.00 1.00 NATOM 1200 NH2 ARG A10517.854 19.308 6.424 1.00 1.00 NATOM 1201 HA ARG A10516.832 15.389 2.281 1.00 1.00 HATOM 1202 HB1 ARG A10514.471 15.533 2.718 1.00 1.00 HATOM 1203 HB2 ARG A10515.249 14.823 4.155 1.00 1.00 HATOM 1204 HG1 ARG A10514.005 17.775 3.978 1.00 1.00 HATOM 1205 HG2 ARG A10513.346 16.301 4.662 1.00 1.00 HATOM 1206 HD1 ARG A10514.146 17.821 6.416 1.00 1.00 HATOM 1207 HD2 ARG A10515.223 16.302 6.247 1.00 1.00 HATOM 1208 HE ARG A10516.253 18.609 4.683 1.00 1.00 HATOM 1209 HH12 ARG A10517.259 18.162 8.677 1.00 1.00 HATOM 1210 HH11 ARG A10515.682 17.702 8.148 1.00 1.00 HATOM 1211 HH22 ARG A10518.490 19.556 7.201 1.00 1.00 HATOM 1212 HH21 ARG A10518.113 19.593 5.446 1.00 1.00 HATOM 1213 HN ARG A10517.091 15.980 5.023 1.00 1.00 HATOM 1214 NGLY A10526.144 17.610 1.076 1.00 1.00 NATOM 1215 CA GLY A10526.082 18.919 0.416 1.00 1.00 CATOM 1216 CGLY A10526.344 18.699 -1.076 1.00 1.00 CATOM 1217 OGLY A10527.496 18.626 -1.468 1.00 1.00 OATOM 1218 HA2 GLY A10526.806 19.612 0.837 1.00 1.00 HATOM 1219 HA1 GLY A10525.124 19.350 0.569 1.00 1.00 HATOM 1220 HN GLY A10525.846 16.823 0.506 1.00 1.00 HATOM 1221 NASN A10535.319 18.634 -1.957 1.00 1.00 NATOM 1222 CA ASN A10535.571 18.512 -3.401 1.00 1.00 CATOM 1223 CASN A10535.958 17.059 -3.749 1.00 1.00 CATOM 1224 OASN A10535.080 16.261 -3.510 1.00 1.00 OATOM 1225 CB ASN A10536.435 19.666 -3.989 1.00 1.00 CATOM 1226 CG ASN A10536.220 19.804 -5.457 1.00 1.00 CATOM 1227 OD1 ASN A10537.032 19.326 -6.235 1.00 1.00 OATOM 1228 ND2 ASN A10535.086 20.449 -5.832 1.00 1.00 NATOM 1229 HA ASN A10534.610 18.552 -3.953 1.00 1.00 HATOM 1230 HB1 ASN A10536.204 20.551 -3.410 1.00 1.00 HATOM 1231 HB2 ASN A10537.529 19.499 -3.827 1.00 1.00 HATOM 1232 HD22 ASN A10534.824 20.564 -6.801 1.00 1.00 HATOM 1233 HD21 ASN A10534.556 20.789 -5.135 1.00 1.00 HATOM 1234 HN ASN A10534.314 18.623 -1.676 1.00 1.00 HATOM 1235 NTYR A10547.115 16.707 -4.319 1.00 1.00 NATOM 1236 CA TYR A10547.490 15.320 -4.492 1.00 1.00 C
ATOM 1237 CTYR A1054 8.413 14.937 -5.648 1.00 1.00 CATOM 1238 OTYR A1054 8.056 14.155 -6.504 1.00 1.00 OATOM 1239 CB TYR A1054 7.946 14.703 -3.110 1.00 1.00 CATOM 1240 CG TYR A1054 8.415 13.228 -3.148 1.00 1.00 CATOM 1241 CD1 TYR A1054 7.971 12.304 -4.079 1.00 1.00 CATOM 1242 CD2 TYR A1054 9.339 12.840 -2.178 1.00 1.00 CATOM 1243 CE1 TYR A1054 8.430 11.001 -4.054 1.00 1.00 CATOM 1244 CE2 TYR A1054 9.883 11.563 -2.224 1.00 1.00 CATOM 1245 CZ TYR A1054 9.480 10.613 -3.186 1.00 1.00 CATOM 1246 OH TYR A1054 10.162 9.431 -3.347 1.00 1.00 OATOM 1247 HA TYR A1054 6.591 14.758 -4.725 1.00 1.00 HATOM 1248 HB2 TYR A1054 8.807 15.291 -2.736 1.00 1.00 HATOM 1249 HB1 TYR A1054 7.162 14.845 -2.378 1.00 1.00 HATOM 1250 HD2 TYR A1054 9.517 13.532 -1.381 1.00 1.00 HATOM 1251 HE2 TYR A1054 10.632 11.272 -1.505 1.00 1.00 HATOM 1252 HE1 TYR A1054 8.050 10.266 -4.751 1.00 1.00 HATOM 1253 HD1 TYR A1054 7.259 12.641 -4.834 1.00 1.00 HATOM 1254 HH TYR A1054 10.018 8.870 -2.588 1.00 1.00 HATOM 1255 HN TYR A1054 7.851 17.300 -4.544 1.00 1.00 HATOM 1256 NARG A1055 9.656 15.467 -5.703 1.00 1.00 NATOM 1257 CA ARG A1055 10.519 15.062 -6.778 1.00 1.00 CATOM 1258 CARG A1055 9.965 15.381 -8.133 1.00 1.00 CATOM 1259 OARG A1055 10.227 14.601 -9.036 1.00 1.00 OATOM 1260 CB ARG A1055 10.921 13.576 -6.733 1.00 1.00 CATOM 1261 CG ARG A1055 11.537 13.150 -5.337 1.00 1.00 CATOM 1262 CD ARG A1055 11.715 11.599 -5.245 1.00 1.00 CATOM 1263 NE ARG A1055 12.681 10.992 -6.145 1.00 1.00 NATOM 1264 CZ ARG A1055 12.890 9.687 -6.214 1.00 1.00 CATOM 1265 NH1 ARG A1055 12.252 8.780 -5.489 1.00 1.00 NATOM 1266 NH2 ARG A1055 13.798 9.351 -7.104 1.00 1.00 NATOM 1267 HA ARG A1055 11.388 15.676 -6.840 1.00 1.00 HATOM 1268 HB1 ARG A1055 10.057 12.926 -6.897 1.00 1.00 HATOM 1269 HB2 ARG A1055 11.634 13.380 -7.558 1.00 1.00 HATOM 1270 HG1 ARG A1055 12.508 13.712 -5.108 1.00 1.00 HATOM 1271 HG2 ARG A1055 10.849 13.428 -4.516 1.00 1.00 HATOM 1272 HD1 ARG A1055 12.053 11.359 -4.190 1.00 1.00 HATOM 1273 HD2 ARG A1055 10.754 11.135 -5.390 1.00 1.00 HATOM 1274 HE ARG A1055 13.173 11.645 -6.742 1.00 1.00 HATOM 1275 HH12 ARG A1055 12.593 7.800 -5.568 1.00 1.00 HATOM 1276 HH11 ARG A1055 11.615 9.066 -4.733 1.00 1.00 HATOM 1277 HH22 ARG A1055 14.051 8.360 -7.286 1.00 1.00 HATOM 1278 HH21 ARG A1055 14.306 10.056 -7.659 1.00 1.00 HATOM 1279 HN ARG A1055 9.988 16.103 -4.991 1.00 1.00 HATOM 1280 NVAL A1056 9.202 16.473 -8.359 1.00 1.00 NATOM 1281 CA VAL A1056 8.770 16.893 -9.686 1.00 1.00 CATOM 1282 CVAL A1056 8.505 18.362 -9.888 1.00 1.00 CATOM 1283 OVAL A1056 9.185 18.953 -10.711 1.00 1.00 OATOM 1284 CB VAL A1056 7.455 16.112 -10.084 1.00 1.00 CATOM 1285 CG1 VAL A1056 7.066 16.502 -11.548 1.00 1.00 CATOM 1286 CG2 VAL A1056 7.591 14.558 -10.032 1.00 1.00 CATOM 1287 HA VAL A1056 9.540 16.579 -10.373 1.00 1.00 HATOM 1288 HB VAL A1056 6.585 16.301 -9.460 1.00 1.00 H
ATOM 1289 HG11 VAL A1056 7.876 16.385 -12.281 1.00 1.00HATOM 1290 HG12 VAL A1056 6.742 17.534 -11.588 1.00 1.00HATOM 1291 HG13 VAL A1056 6.203 15.836 -11.843 1.00 1.00HATOM 1292 HG21 VAL A1056 8.332 14.223 -10.798 1.00 1.00HATOM 1293 HG22 VAL A1056 7.835 14.250 -9.060 1.00 1.00HATOM 1294 HG23 VAL A1056 6.625 14.067 -10.181 1.00 1.00HATOM 1295 HNVAL A1056 8.993 17.132 -7.618 1.00 1.00HATOM 1296 N SER A1057 7.509 18.936 -9.155 1.00 1.00NATOM 1297 CASER A1057 6.985 20.332 -9.409 1.00 1.00CATOM 1298 C SER A1057 5.496 20.339 -9.523 1.00 1.00CATOM 1299 O SER A1057 4.763 20.349 -8.522 1.00 1.00OATOM 1300 CBSER A1057 7.699 21.255 -10.463 1.00 1.00CATOM 1301 OGSER A1057 7.564 20.901 -11.794 1.00 1.00OATOM 1302 HASER A1057 7.208 20.805 -8.416 1.00 1.00HATOM 1303 HB1 SER A1057 7.205 22.198 -10.334 1.00 1.00HATOM 1304 HB2 SER A1057 8.761 21.405 -10.238 1.00 1.00HATOM 1305 HGSER A1057 7.996 20.093 -12.041 1.00 1.00HATOM 1306 HNSER A1057 7.120 18.415 -8.346 1.00 1.00HATOM 1307 N TRP A1058 4.870 20.373 -10.727 1.00 1.00NATOM 1308 CATRP A1058 3.445 20.509 -10.895 1.00 1.00CATOM 1309 C TRP A1058 3.058 19.984 -12.235 1.00 1.00CATOM 1310 O TRP A1058 2.866 20.800 -13.120 1.00 1.00OATOM 1311 CBTRP A1058 3.179 22.028 -10.784 1.00 1.00CATOM 1312 CGTRP A1058 3.665 22.687 -9.506 1.00 1.00CATOM 1313 CD1 TRP A1058 4.699 23.599 -9.341 1.00 1.00CATOM 1314 CD2 TRP A1058 3.147 22.472 -8.117 1.00 1.00CATOM 1315 NE1 TRP A1058 4.850 23.909 -8.074 1.00 1.00NATOM 1316 CE2 TRP A1058 3.922 23.285 -7.329 1.00 1.00CATOM 1317 CE3 TRP A1058 2.161 21.666 -7.574 1.00 1.00CATOM 1318 CZ2 TRP A1058 3.753 23.389 -5.945 1.00 1.00CATOM 1319 CZ3 TRP A1058 1.987 21.671 -6.191 1.00 1.00CATOM 1320 CH2 TRP A1058 2.718 22.613 -5.396 1.00 1.00CATOM 1321 HATRP A1058 2.925 19.952 -10.114 1.00 1.00HATOM 1322 HB1 TRP A1058 3.696 22.603 -11.620 1.00 1.00HATOM 1323 HB2 TRP A1058 2.095 22.175 -10.851 1.00 1.00HATOM 1324 HE1 TRP A1058 5.553 24.563 -7.694 1.00 1.00HATOM 1325 HD1 TRP A1058 5.344 24.056 -10.071 1.00 1.00HATOM 1326 HZ2 TRP A1058 4.426 24.029 -5.359 1.00 1.00HATOM 1327 HH2 TRP A1058 2.452 22.706 -4.338 1.00 1.00HATOM 1328 HZ3 TRP A1058 1.313 21.006 -5.640 1.00 1.00HATOM 1329 HE3 TRP A1058 1.544 21.113 -8.208 1.00 1.00HATOM 1330 HNTRP A1058 5.490 20.361 -11.529 1.00 1.00HATOM 1331 N PRO A1059 2.987 18.624 -12.476 1.00 1.00NATOM 1332 CAPRO A1059 2.786 18.260 -13.879 1.00 1.00CATOM 1333 C PRO A1059 1.323 18.384 -14.144 1.00 1.00CATOM 1334 O PRO A1059 0.689 17.360 -13.918 1.00 1.00OATOM 1335 CBPRO A1059 3.350 16.847 -13.882 1.00 1.00CATOM 1336 CGPRO A1059 3.076 16.423 -12.412 1.00 1.00CATOM 1337 CDPRO A1059 3.206 17.612 -11.479 1.00 1.00CATOM 1338 HAPRO A1059 3.333 18.922 -14.560 1.00 1.00HATOM 1339 HD2 PRO A1059 2.414 17.616 -10.700 1.00 1.00HATOM 1340 HD1 PRO A1059 4.194 17.753 -11.053 1.00 1.00H
ATOM 1341 HG2 PRO A1059 3.788 15.709 -12.129 1.00 1.00 HATOM 1342 HG1 PRO A1059 2.074 15.963 -12.318 1.00 1.00 HATOM 1343 HB1 PRO A1059 2.920 16.164 -14.655 1.00 1.00 HATOM 1344 HB2 PRO A1059 4.451 16.917 -14.010 1.00 1.00 HATOM 1345 N LYS A1060 0.768 19.588 -14.556 1.00 1.00 NATOM 1346 CA LYS A1060 -0.669 19.695 -14.694 1.00 1.00 CATOM 1347 C LYS A1060 -1.179 19.888 -16.101 1.00 1.00 CATOM 1348 O LYS A1060 -0.397 20.348 -16.950 1.00 1.00 OATOM 1349 CB LYS A1060 -1.126 20.947 -13.863 1.00 1.00 CATOM 1350 CG LYS A1060 -0.898 20.840 -12.321 1.00 1.00 CATOM 1351 CD LYS A1060 -1.557 22.027 -11.553 1.00 1.00 CATOM 1352 CE LYS A1060 -1.442 21.706 -10.044 1.00 1.00 CATOM 1353 NZ LYS A1060 -2.141 20.465 -9.627 1.00 1.00 NATOM 1354 HA LYS A1060 -1.167 18.737 -14.326 1.00 1.00 HATOM 1355 HB1 LYS A1060 -0.616 21.829 -14.236 1.00 1.00 HATOM 1356 HB2 LYS A1060 -2.146 20.983 -14.077 1.00 1.00 HATOM 1357 HG1 LYS A1060 -1.307 19.896 -12.043 1.00 1.00 HATOM 1358 HG2 LYS A1060 0.200 20.828 -12.094 1.00 1.00 HATOM 1359 HD1 LYS A1060 -1.133 22.988 -11.845 1.00 1.00 HATOM 1360 HD2 LYS A1060 -2.593 22.015 -11.860 1.00 1.00 HATOM 1361 HE1 LYS A1060 -1.827 22.565 -9.461 1.00 1.00 HATOM 1362 HE2 LYS A1060 -0.362 21.578 -9.737 1.00 1.00 HATOM 1363 HZ1 LYS A1060 -3.201 20.439 -9.913 1.00 1.00 HATOM 1364 HZ2 LYS A1060 -1.727 19.517 -10.033 1.00 1.00 HATOM 1365 HZ3 LYS A1060 -2.045 20.337 -8.558 1.00 1.00 HATOM 1366 HN LYS A1060 1.338 20.411 -14.681 1.00 1.00 HATOM 1367 N PHE A1061 -2.443 19.579 -16.367 1.00 1.00 NATOM 1368 CA PHE A1061 -3.006 19.744 -17.671 1.00 1.00 CATOM 1369 C PHE A1061 -4.526 19.639 -17.532 1.00 1.00 CATOM 1370 O PHE A1061 -5.023 18.972 -16.635 1.00 1.00 OATOM 1371 CB PHE A1061 -2.537 18.663 -18.668 1.00 1.00 CATOM 1372 CG PHE A1061 -3.201 18.897 -20.024 1.00 1.00 CATOM 1373 CD1 PHE A1061 -4.235 18.094 -20.548 1.00 1.00 CATOM 1374 CD2 PHE A1061 -2.699 19.923 -20.879 1.00 1.00 CATOM 1375 CE1 PHE A1061 -4.803 18.328 -21.816 1.00 1.00 CATOM 1376 CE2 PHE A1061 -3.329 20.172 -22.124 1.00 1.00 CATOM 1377 CZ PHE A1061 -4.398 19.402 -22.593 1.00 1.00 CATOM 1378 HA PHE A1061 -2.705 20.716 -18.149 1.00 1.00 HATOM 1379 HB1 PHE A1061 -1.450 18.746 -18.725 1.00 1.00 HATOM 1380 HB2 PHE A1061 -2.862 17.631 -18.258 1.00 1.00 HATOM 1381 HD2 PHE A1061 -1.871 20.513 -20.596 1.00 1.00 HATOM 1382 HE2 PHE A1061 -2.987 21.030 -22.782 1.00 1.00 HATOM 1383 HZ PHE A1061 -4.890 19.642 -23.520 1.00 1.00 HATOM 1384 HE1 PHE A1061 -5.537 17.628 -22.184 1.00 1.00 HATOM 1385 HD1 PHE A1061 -4.632 17.304 -19.909 1.00 1.00 HATOM 1386 HN PHE A1061 -3.049 19.272 -15.627 1.00 1.00 HATOM 1387 N ALA A1062 -5.376 20.284 -18.349 1.00 1.00 NATOM 1388 CA ALA A1062 -6.871 20.160 -18.256 1.00 1.00 CATOM 1389 C ALA A1062 -7.497 18.904 -18.742 1.00 1.00 CATOM 1390 O ALA A1062 -7.107 18.453 -19.815 1.00 1.00 OATOM 1391 CB ALA A1062 -7.550 21.504 -18.742 1.00 1.00 CATOM 1392 HA ALA A1062 -7.044 20.137 -17.179 1.00 1.00 H
ATOM 1393 HB1 ALA A1062-8.643 21.417 -18.713 1.00 1.00 HATOM 1394 HB2 ALA A1062-7.194 22.384 -18.132 1.00 1.00 HATOM 1395 HB3 ALA A1062-7.335 21.666 -19.792 1.00 1.00 HATOM 1396 HN ALA A1062-4.973 20.784 -19.105 1.00 1.00 HATOM 1397 NVAL A1063-8.508 18.281 -18.001 1.00 1.00 NATOM 1398 CA VAL A1063-9.127 16.996 -18.375 1.00 1.00 CATOM 1399 CVAL A1063-10.646 17.053 -18.223 1.00 1.00 CATOM 1400 OVAL A1063-11.223 16.324 -17.448 1.00 1.00 OATOM 1401 CB VAL A1063-8.458 15.798 -17.605 1.00 1.00 CATOM 1402 CG1 VAL A1063-8.673 14.424 -18.315 1.00 1.00 CATOM 1403 CG2 VAL A1063-6.924 15.981 -17.482 1.00 1.00 CATOM 1404 HA VAL A1063-8.935 16.772 -19.411 1.00 1.00 HATOM 1405 HB VAL A1063-8.824 15.769 -16.567 1.00 1.00 HATOM 1406 HG11 VAL A1063-8.184 14.491 -19.271 1.00 1.00 HATOM 1407 HG12 VAL A1063-8.254 13.558 -17.758 1.00 1.00 HATOM 1408 HG13 VAL A1063-9.734 14.273 -18.452 1.00 1.00 HATOM 1409 HG21 VAL A1063-6.694 16.708 -16.721 1.00 1.00 HATOM 1410 HG22 VAL A1063-6.380 15.014 -17.263 1.00 1.00 HATOM 1411 HG23 VAL A1063-6.495 16.276 -18.419 1.00 1.00 HATOM 1412 HN VAL A1063-8.862 18.752 -17.242 1.00 1.00 HATOM 1413 NPRO A1064-11.422 17.810 -19.050 1.00 1.00 NATOM 1414 CA PRO A1064-12.896 17.729 -19.072 1.00 1.00 CATOM 1415 CPRO A1064-13.379 16.327 -19.270 1.00 1.00 CATOM 1416 OPRO A1064-14.451 16.018 -18.805 1.00 1.00 OATOM 1417 CB PRO A1064-13.215 18.655 -20.320 1.00 1.00 CATOM 1418 CG PRO A1064-12.035 19.651 -20.380 1.00 1.00 CATOM 1419 CD PRO A1064-10.832 18.727 -20.001 1.00 1.00 CATOM 1420 HA PRO A1064-13.353 18.213 -18.137 1.00 1.00 HATOM 1421 HD2 PRO A1064-10.376 18.193 -20.883 1.00 1.00 HATOM 1422 HD1 PRO A1064-10.059 19.413 -19.567 1.00 1.00 HATOM 1423 HG2 PRO A1064-11.862 20.242 -21.329 1.00 1.00 HATOM 1424 HG1 PRO A1064-12.194 20.321 -19.520 1.00 1.00 HATOM 1425 HB1 PRO A1064-13.191 18.082 -21.270 1.00 1.00 HATOM 1426 HB2 PRO A1064-14.212 19.142 -20.220 1.00 1.00 HATOM 1427 NASN A1065-12.568 15.451 -19.888 1.00 1.00 NATOM 1428 CA ASN A1065-12.982 14.084 -20.047 1.00 1.00 CATOM 1429 CASN A1065-13.510 13.475 -18.724 1.00 1.00 CATOM 1430 OASN A1065-14.505 12.758 -18.779 1.00 1.00 OATOM 1431 CB ASN A1065-11.938 13.171 -20.681 1.00 1.00 CATOM 1432 CG ASN A1065-12.414 11.736 -20.606 1.00 1.00 CATOM 1433 OD1 ASN A1065-13.417 11.462 -21.244 1.00 1.00 OATOM 1434 ND2 ASN A1065-11.740 10.868 -19.838 1.00 1.00 NATOM 1435 HA ASN A1065-13.846 14.065 -20.750 1.00 1.00 HATOM 1436 HB1 ASN A1065-11.873 13.466 -21.790 1.00 1.00 HATOM 1437 HB2 ASN A1065-10.984 13.289 -20.213 1.00 1.00 HATOM 1438 HD22 ASN A1065-11.938 9.867 -19.863 1.00 1.00 HATOM 1439 HD21 ASN A1065-10.931 11.116 -19.276 1.00 1.00 HATOM 1440 HN ASN A1065-11.682 15.752 -20.268 1.00 1.00 HATOM 1441 NLEU A1066-12.865 13.747 -17.595 1.00 1.00 NATOM 1442 CA LEU A1066-13.406 13.181 -16.401 1.00 1.00 CATOM 1443 CLEU A1066-14.839 13.581 -16.191 1.00 1.00 CATOM 1444 OLEU A1066-15.673 12.707 -16.066 1.00 1.00 O
ATOM 1445 CB LEU A1066 -12.637 13.545 -15.112 1.00 1.00CATOM 1446 CG LEU A1066 -11.130 13.449 -15.083 1.00 1.00CATOM 1447 CD1 LEU A1066 -10.571 13.752 -13.678 1.00 1.00CATOM 1448 CD2 LEU A1066 -10.473 12.150 -15.604 1.00 1.00CATOM 1449 HA LEU A1066 -13.235 12.093 -16.596 1.00 1.00HATOM 1450 HB1 LEU A1066 -12.862 14.580 -14.804 1.00 1.00HATOM 1451 HB2 LEU A1066 -13.011 12.894 -14.286 1.00 1.00HATOM 1452 HG LEU A1066 -10.739 14.317 -15.655 1.00 1.00HATOM 1453 HD21 LEU A1066 -10.727 11.316 -14.940 1.00 1.00HATOM 1454 HD22 LEU A1066 -10.799 11.894 -16.596 1.00 1.00HATOM 1455 HD23 LEU A1066 -9.36412.291 -15.642 1.00 1.00HATOM 1456 HD11 LEU A1066 -9.52613.536 -13.570 1.00 1.00HATOM 1457 HD12 LEU A1066 -10.796 14.780 -13.332 1.00 1.00HATOM 1458 HD13 LEU A1066 -11.014 13.114 -12.952 1.00 1.00HATOM 1459 HN LEU A1066 -12.041 14.308 -17.614 1.00 1.00HATOM 1460 NGLN A1067 -15.150 14.911 -16.256 1.00 1.00NATOM 1461 CA GLN A1067 -16.538 15.356 -16.167 1.00 1.00CATOM 1462 CGLN A1067 -17.365 14.534 -17.142 1.00 1.00CATOM 1463 OGLN A1067 -18.418 14.037 -16.810 1.00 1.00OATOM 1464 CB GLN A1067 -16.703 16.830 -16.495 1.00 1.00CATOM 1465 CG GLN A1067 -18.066 17.498 -16.197 1.00 1.00CATOM 1466 CD GLN A1067 -18.107 18.949 -16.604 1.00 1.00CATOM 1467 OE1 GLN A1067 -18.791 19.271 -17.575 1.00 1.00OATOM 1468 NE2 GLN A1067 -17.347 19.886 -16.047 1.00 1.00NATOM 1469 HA GLN A1067 -16.907 15.133 -15.198 1.00 1.00HATOM 1470 HB1 GLN A1067 -16.002 17.396 -15.924 1.00 1.00HATOM 1471 HB2 GLN A1067 -16.447 17.028 -17.540 1.00 1.00HATOM 1472 HG1 GLN A1067 -18.915 16.973 -16.654 1.00 1.00HATOM 1473 HG2 GLN A1067 -18.202 17.434 -15.107 1.00 1.00HATOM 1474 HE22 GLN A1067 -17.377 20.838 -16.366 1.00 1.00HATOM 1475 HE21 GLN A1067 -16.813 19.704 -15.203 1.00 1.00HATOM 1476 HN GLN A1067 -14.432 15.621 -16.385 1.00 1.00HATOM 1477 NSER A1068 -16.889 14.337 -18.407 1.00 1.00NATOM 1478 CA SER A1068 -17.773 13.622 -19.384 1.00 1.00CATOM 1479 CSER A1068 -18.008 12.165 -19.084 1.00 1.00CATOM 1480 OSER A1068 -19.095 11.592 -19.226 1.00 1.00OATOM 1481 CB SER A1068 -17.309 13.909 -20.799 1.00 1.00CATOM 1482 OG SER A1068 -18.173 13.426 -21.871 1.00 1.00OATOM 1483 HA SER A1068 -18.808 14.094 -19.266 1.00 1.00HATOM 1484 HB1 SER A1068 -17.311 14.988 -20.829 1.00 1.00HATOM 1485 HB2 SER A1068 -16.295 13.469 -20.861 1.00 1.00HATOM 1486 HG SER A1068 -19.085 13.706 -21.793 1.00 1.00HATOM 1487 HN SER A1068 -15.985 14.647 -18.638 1.00 1.00HATOM 1488 NLEU A1069 -16.982 11.406 -18.611 1.00 1.00NATOM 1489 CA LEU A1069 -17.213 10.002 -18.299 1.00 1.00CATOM 1490 CLEU A1069 -18.036 9.969 -17.037 1.00 1.00CATOM 1491 OLEU A1069 -18.896 9.116 -16.855 1.00 1.00OATOM 1492 CB LEU A1069 -15.916 9.197 -18.064 1.00 1.00CATOM 1493 CG LEU A1069 -14.996 8.946 -19.312 1.00 1.00CATOM 1494 CD1 LEU A1069 -13.834 8.026 -18.890 1.00 1.00CATOM 1495 CD2 LEU A1069 -15.738 8.383 -20.580 1.00 1.00CATOM 1496 HA LEU A1069 -17.773 9.460 -19.077 1.00 1.00H
ATOM 1497 HB1 LEU A1069 -15.378 9.642 -17.234 1.00 1.00HATOM 1498 HB2 LEU A1069 -16.288 8.271 -17.596 1.00 1.00HATOM 1499 HG LEU A1069 -14.643 9.969 -19.480 1.00 1.00HATOM 1500 HD21 LEU A1069 -15.985 7.349 -20.479 1.00 1.00HATOM 1501 HD22 LEU A1069 -16.611 8.972 -20.865 1.00 1.00HATOM 1502 HD23 LEU A1069 -14.997 8.453 -21.386 1.00 1.00HATOM 1503 HD11 LEU A1069 -13.307 8.421 -17.997 1.00 1.00HATOM 1504 HD12 LEU A1069 -14.233 7.001 -18.707 1.00 1.00HATOM 1505 HD13 LEU A1069 -13.094 7.905 -19.712 1.00 1.00HATOM 1506 HN LEU A1069 -16.145 11.855 -18.331 1.00 1.00HATOM 1507 NTHR A1070 -17.788 10.870 -16.029 1.00 1.00NATOM 1508 CA THR A1070 -18.693 10.799 -14.854 1.00 1.00CATOM 1509 CTHR A1070 -20.092 11.267 -15.233 1.00 1.00CATOM 1510 OTHR A1070 -21.049 10.624 -14.863 1.00 1.00OATOM 1511 CB THR A1070 -18.158 11.669 -13.675 1.00 1.00CATOM 1512 OG1 THR A1070 -17.813 12.974 -14.087 1.00 1.00OATOM 1513 CG2 THR A1070 -16.890 10.959 -13.143 1.00 1.00CATOM 1514 HA THR A1070 -18.734 9.770 -14.454 1.00 1.00HATOM 1515 HB THR A1070 -18.878 11.684 -12.864 1.00 1.00HATOM 1516 HG1 THR A1070 -18.524 13.554 -14.323 1.00 1.00HATOM 1517 HG23 THR A1070 -17.042 9.976 -12.604 1.00 1.00HATOM 1518 HG21 THR A1070 -16.118 10.871 -13.957 1.00 1.00HATOM 1519 HG22 THR A1070 -16.506 11.619 -12.344 1.00 1.00HATOM 1520 HN THR A1070 -17.178 11.648 -16.083 1.00 1.00HATOM 1521 NASN A1071 -20.295 12.290 -16.075 1.00 1.00NATOM 1522 CA ASN A1071 -21.620 12.591 -16.515 1.00 1.00CATOM 1523 CASN A1071 -22.227 11.509 -17.359 1.00 1.00CATOM 1524 OASN A1071 -23.437 11.327 -17.333 1.00 1.00OATOM 1525 CB ASN A1071 -21.598 13.845 -17.332 1.00 1.00CATOM 1526 CG ASN A1071 -23.056 14.261 -17.569 1.00 1.00CATOM 1527 OD1 ASN A1071 -23.600 14.063 -18.637 1.00 1.00OATOM 1528 ND2 ASN A1071 -23.723 14.851 -16.551 1.00 1.00NATOM 1529 HA ASN A1071 -22.238 12.759 -15.608 1.00 1.00HATOM 1530 HB1 ASN A1071 -21.075 14.705 -16.910 1.00 1.00HATOM 1531 HB2 ASN A1071 -21.101 13.620 -18.303 1.00 1.00HATOM 1532 HD22 ASN A1071 -24.645 15.100 -16.739 1.00 1.00HATOM 1533 HD21 ASN A1071 -23.358 15.069 -15.695 1.00 1.00HATOM 1534 HN ASN A1071 -19.501 12.752 -16.457 1.00 1.00HATOM 1535 NLEU A1072 -21.443 10.715 -18.128 1.00 1.00NATOM 1536 CA LEU A1072 -22.077 9.573 -18.851 1.00 1.00CATOM 1537 CLEU A1072 -22.399 8.431 -17.907 1.00 1.00CATOM 1538 OLEU A1072 -23.510 7.911 -18.062 1.00 1.00OATOM 1539 CB LEU A1072 -21.249 9.008 -20.007 1.00 1.00CATOM 1540 CG LEU A1072 -21.003 9.901 -21.270 1.00 1.00CATOM 1541 CD1 LEU A1072 -19.896 9.301 -22.229 1.00 1.00CATOM 1542 CD2 LEU A1072 -22.365 10.046 -22.073 1.00 1.00CATOM 1543 HA LEU A1072 -23.022 9.899 -19.273 1.00 1.00HATOM 1544 HB1 LEU A1072 -20.242 8.828 -19.581 1.00 1.00HATOM 1545 HB2 LEU A1072 -21.690 8.031 -20.312 1.00 1.00HATOM 1546 HG LEU A1072 -20.578 10.873 -20.955 1.00 1.00HATOM 1547 HD21 LEU A1072 -22.774 9.117 -22.385 1.00 1.00HATOM 1548 HD22 LEU A1072 -23.130 10.617 -21.471 1.00 1.00H
ATOM 1549 HD23 LEU A1072 -22.140 10.562 -23.023 1.00 1.00 HATOM 1550 HD11 LEU A1072 -20.204 8.316 -22.609 1.00 1.00 HATOM 1551 HD12 LEU A1072 -19.671 10.002 -23.055 1.00 1.00 HATOM 1552 HD13 LEU A1072 -18.981 9.241 -21.589 1.00 1.00 HATOM 1553 HN LEU A1072 -20.483 10.991 -18.262 1.00 1.00 HATOM 1554 NLEU A1073 -21.457 8.098 -17.000 1.00 1.00 NATOM 1555 CA LEU A1073 -21.692 6.990 -16.034 1.00 1.00 CATOM 1556 CLEU A1073 -22.939 7.405 -15.257 1.00 1.00 CATOM 1557 OLEU A1073 -23.826 6.566 -15.029 1.00 1.00 OATOM 1558 CB LEU A1073 -20.515 6.801 -15.044 1.00 1.00 CATOM 1559 CG LEU A1073 -20.793 5.854 -13.848 1.00 1.00 CATOM 1560 CD1 LEU A1073 -21.212 4.400 -14.230 1.00 1.00 CATOM 1561 CD2 LEU A1073 -19.526 5.798 -12.932 1.00 1.00 CATOM 1562 HA LEU A1073 -21.936 6.120 -16.628 1.00 1.00 HATOM 1563 HB1 LEU A1073 -19.698 6.473 -15.752 1.00 1.00 HATOM 1564 HB2 LEU A1073 -20.231 7.787 -14.600 1.00 1.00 HATOM 1565 HG LEU A1073 -21.642 6.346 -13.288 1.00 1.00 HATOM 1566 HD21 LEU A1073 -19.253 6.821 -12.562 1.00 1.00 HATOM 1567 HD22 LEU A1073 -19.741 5.071 -12.123 1.00 1.00 HATOM 1568 HD23 LEU A1073 -18.693 5.465 -13.507 1.00 1.00 HATOM 1569 HD11 LEU A1073 -21.501 3.850 -13.323 1.00 1.00 HATOM 1570 HD12 LEU A1073 -22.042 4.402 -14.922 1.00 1.00 HATOM 1571 HD13 LEU A1073 -20.367 3.859 -14.717 1.00 1.00 HATOM 1572 HN LEU A1073 -20.593 8.611 -16.946 1.00 1.00 HATOM 1573 NSER A1074 -23.105 8.663 -14.778 1.00 1.00 NATOM 1574 CA SER A1074 -24.270 9.037 -13.974 1.00 1.00 CATOM 1575 CSER A1074 -25.586 8.734 -14.640 1.00 1.00 CATOM 1576 OSER A1074 -26.580 8.398 -14.004 1.00 1.00 OATOM 1577 CB SER A1074 -24.189 10.516 -13.553 1.00 1.00 CATOM 1578 OG SER A1074 -24.158 11.449 -14.688 1.00 1.00 OATOM 1579 HA SER A1074 -24.195 8.412 -13.040 1.00 1.00 HATOM 1580 HB1 SER A1074 -25.012 10.675 -12.811 1.00 1.00 HATOM 1581 HB2 SER A1074 -23.255 10.616 -12.985 1.00 1.00 HATOM 1582 HG SER A1074 -24.910 11.421 -15.263 1.00 1.00 HATOM 1583 HN SER A1074 -22.440 9.376 -15.019 1.00 1.00 HATOM 1584 NSER A1075 -25.671 8.822 -16.003 1.00 1.00 NATOM 1585 CA SER A1075 -26.908 8.384 -16.683 1.00 1.00 CATOM 1586 CSER A1075 -27.038 6.932 -16.834 1.00 1.00 CATOM 1587 OSER A1075 -28.150 6.547 -17.078 1.00 1.00 OATOM 1588 CB SER A1075 -27.145 9.028 -18.092 1.00 1.00 CATOM 1589 OG SER A1075 -26.213 8.440 -19.054 1.00 1.00 OATOM 1590 HA SER A1075 -27.751 8.642 -16.058 1.00 1.00 HATOM 1591 HB1 SER A1075 -28.171 8.861 -18.439 1.00 1.00 HATOM 1592 HB2 SER A1075 -27.003 10.124 -17.930 1.00 1.00 HATOM 1593 HG SER A1075 -25.287 8.485 -18.823 1.00 1.00 HATOM 1594 HN SER A1075 -24.852 9.122 -16.485 1.00 1.00 HATOM 1595 NASN A1076 -26.015 6.093 -16.720 1.00 1.00 NATOM 1596 CA ASN A1076 -26.212 4.668 -17.150 1.00 1.00 CATOM 1597 CASN A1076 -27.100 3.942 -16.086 1.00 1.00 CATOM 1598 OASN A1076 -27.814 3.057 -16.527 1.00 1.00 OATOM 1599 CB ASN A1076 -24.893 3.876 -17.506 1.00 1.00 CATOM 1600 CG ASN A1076 -24.383 4.158 -18.910 1.00 1.00 C
ATOM 1601 OD1 ASN A1076 -24.482 3.238 -19.682 1.00 1.00 OATOM 1602 ND2 ASN A1076 -23.746 5.344 -19.196 1.00 1.00 NATOM 1603 HA ASN A1076 -26.789 4.638 -18.082 1.00 1.00 HATOM 1604 HB1 ASN A1076 -24.145 4.157 -16.738 1.00 1.00 HATOM 1605 HB2 ASN A1076 -24.987 2.789 -17.418 1.00 1.00 HATOM 1606 HD22 ASN A1076 -23.304 5.548 -20.090 1.00 1.00 HATOM 1607 HD21 ASN A1076 -23.665 6.073 -18.509 1.00 1.00 HATOM 1608 HN ASN A1076 -25.082 6.410 -16.529 1.00 1.00 HATOM 1609 NLEU A1077 -26.892 4.268 -14.798 1.00 1.00 NATOM 1610 CA LEU A1077 -27.718 3.742 -13.686 1.00 1.00 CATOM 1611 CLEU A1077 -27.705 2.229 -13.514 1.00 1.00 CATOM 1612 OLEU A1077 -27.660 1.448 -14.460 1.00 1.00 OATOM 1613 CB LEU A1077 -29.119 4.307 -13.693 1.00 1.00 CATOM 1614 CG LEU A1077 -29.131 5.881 -13.614 1.00 1.00 CATOM 1615 CD1 LEU A1077 -30.570 6.428 -13.896 1.00 1.00 CATOM 1616 CD2 LEU A1077 -28.611 6.504 -12.313 1.00 1.00 CATOM 1617 HA LEU A1077 -27.185 4.095 -12.806 1.00 1.00 HATOM 1618 HB1 LEU A1077 -29.700 3.805 -12.898 1.00 1.00 HATOM 1619 HB2 LEU A1077 -29.574 4.040 -14.668 1.00 1.00 HATOM 1620 HG LEU A1077 -28.487 6.203 -14.444 1.00 1.00 HATOM 1621 HD21 LEU A1077 -29.214 6.241 -11.413 1.00 1.00 HATOM 1622 HD22 LEU A1077 -27.534 6.306 -12.105 1.00 1.00 HATOM 1623 HD23 LEU A1077 -28.764 7.603 -12.335 1.00 1.00 HATOM 1624 HD11 LEU A1077 -31.246 5.940 -13.192 1.00 1.00 HATOM 1625 HD12 LEU A1077 -30.777 6.215 -14.975 1.00 1.00 HATOM 1626 HD13 LEU A1077 -30.554 7.543 -13.754 1.00 1.00 HATOM 1627 HN LEU A1077 -26.184 4.923 -14.573 1.00 1.00 HATOM 1628 NSER A1078 -27.860 1.697 -12.237 1.00 1.00 NATOM 1629 CA SER A1078 -28.170 0.278 -12.056 1.00 1.00 CATOM 1630 CSER A1078 -27.111 -0.740 -12.442 1.00 1.00 CATOM 1631 OSER A1078 -27.277 -1.430 -13.423 1.00 1.00 OATOM 1632 CB SER A1078 -29.579 0.024 -12.646 1.00 1.00 CATOM 1633 OG SER A1078 -29.988 -1.351 -12.420 1.00 1.00 OATOM 1634 HA SER A1078 -28.324 0.115 -10.945 1.00 1.00 HATOM 1635 HB1 SER A1078 -30.237 0.799 -12.194 1.00 1.00 HATOM 1636 HB2 SER A1078 -29.572 0.240 -13.724 1.00 1.00 HATOM 1637 HG SER A1078 -30.863 -1.441 -12.775 1.00 1.00 HATOM 1638 HN SER A1078 -27.887 2.327 -11.431 1.00 1.00 HATOM 1639 NTRP A1079 -25.978 -0.964 -11.681 1.00 1.00 NATOM 1640 CA TRP A1079 -24.970 -1.975 -12.051 1.00 1.00 CATOM 1641 CTRP A1079 -23.943 -2.343 -10.975 1.00 1.00 CATOM 1642 OTRP A1079 -24.295 -3.091 -10.115 1.00 1.00 OATOM 1643 CB TRP A1079 -24.363 -1.916 -13.507 1.00 1.00 CATOM 1644 CG TRP A1079 -24.015 -0.585 -14.068 1.00 1.00 CATOM 1645 CD1 TRP A1079 -24.469 0.642 -13.698 1.00 1.00 CATOM 1646 CD2 TRP A1079 -23.076 -0.401 -15.236 1.00 1.00 CATOM 1647 NE1 TRP A1079 -23.955 1.511 -14.502 1.00 1.00 NATOM 1648 CE2 TRP A1079 -23.161 0.950 -15.404 1.00 1.00 CATOM 1649 CE3 TRP A1079 -22.270 -1.211 -16.007 1.00 1.00 CATOM 1650 CZ2 TRP A1079 -22.431 1.550 -16.461 1.00 1.00 CATOM 1651 CZ3 TRP A1079 -21.596 -0.625 -17.088 1.00 1.00 CATOM 1652 CH2 TRP A1079 -21.705 0.732 -17.375 1.00 1.00 C
ATOM 1653 HA TRP A1079 -25.500 -2.912 -12.104 1.00 1.00 HATOM 1654 HB1 TRP A1079 -23.435 -2.509 -13.504 1.00 1.00 HATOM 1655 HB2 TRP A1079 -24.991 -2.388 -14.328 1.00 1.00 HATOM 1656 HE1 TRP A1079 -24.114 2.532 -14.425 1.00 1.00 HATOM 1657 HD1 TRP A1079 -25.080 0.952 -12.854 1.00 1.00 HATOM 1658 HZ2 TRP A1079 -22.428 2.616 -16.591 1.00 1.00 HATOM 1659 HH2 TRP A1079 -21.252 1.117 -18.249 1.00 1.00 HATOM 1660 HZ3 TRP A1079 -20.920 -1.220 -17.690 1.00 1.00 HATOM 1661 HE3 TRP A1079 -22.054 -2.266 -15.801 1.00 1.00 HATOM 1662 HN TRP A1079 -25.762 -0.423 -10.837 1.00 1.00 HATOM 1663 NLEU A1080 -22.700 -1.792 -11.089 1.00 1.00 NATOM 1664 CA LEU A1080 -21.584 -2.254 -10.268 1.00 1.00 CATOM 1665 CLEU A1080 -20.811 -1.101 -9.688 1.00 1.00 CATOM 1666 OLEU A1080 -20.950 0.005 -10.133 1.00 1.00 OATOM 1667 CB LEU A1080 -20.441 -3.016 -11.017 1.00 1.00 CATOM 1668 CG LEU A1080 -20.826 -4.258 -11.883 1.00 1.00 CATOM 1669 CD1 LEU A1080 -19.588 -4.881 -12.618 1.00 1.00 CATOM 1670 CD2 LEU A1080 -21.377 -5.336 -10.920 1.00 1.00 CATOM 1671 HA LEU A1080 -21.889 -2.916 -9.459 1.00 1.00 HATOM 1672 HB1 LEU A1080 -19.960 -2.303 -11.744 1.00 1.00 HATOM 1673 HB2 LEU A1080 -19.667 -3.281 -10.340 1.00 1.00 HATOM 1674 HG LEU A1080 -21.643 -4.010 -12.587 1.00 1.00 HATOM 1675 HD21 LEU A1080 -22.341 -5.020 -10.582 1.00 1.00 HATOM 1676 HD22 LEU A1080 -20.689 -5.488 -10.085 1.00 1.00 HATOM 1677 HD23 LEU A1080 -21.477 -6.373 -11.317 1.00 1.00 HATOM 1678 HD11 LEU A1080 -18.733 -5.130 -11.971 1.00 1.00 HATOM 1679 HD12 LEU A1080 -19.232 -4.119 -13.335 1.00 1.00 HATOM 1680 HD13 LEU A1080 -19.893 -5.784 -13.153 1.00 1.00 HATOM 1681 HN LEU A1080 -22.490 -1.072 -11.757 1.00 1.00 HATOM 1682 NSER A1081 -19.941 -1.344 -8.681 1.00 1.00 NATOM 1683 CA SER A1081 -18.991 -0.360 -8.239 1.00 1.00 CATOM 1684 CSER A1081 -17.758 -1.005 -7.602 1.00 1.00 CATOM 1685 OSER A1081 -17.930 -1.894 -6.811 1.00 1.00 OATOM 1686 CB SER A1081 -19.537 0.505 -7.057 1.00 1.00 CATOM 1687 OG SER A1081 -20.625 1.320 -7.482 1.00 1.00 OATOM 1688 HA SER A1081 -18.636 0.244 -9.061 1.00 1.00 HATOM 1689 HB1 SER A1081 -18.758 1.185 -6.666 1.00 1.00 HATOM 1690 HB2 SER A1081 -19.856 -0.125 -6.196 1.00 1.00 HATOM 1691 HG SER A1081 -21.039 1.885 -6.839 1.00 1.00 HATOM 1692 HN SER A1081 -20.022 -2.240 -8.215 1.00 1.00 HATOM 1693 NLEU A1082 -16.475 -0.608 -7.969 1.00 1.00 NATOM 1694 CA LEU A1082 -15.313 -1.365 -7.516 1.00 1.00 CATOM 1695 CLEU A1082 -14.034 -0.533 -7.285 1.00 1.00 CATOM 1696 OLEU A1082 -13.521 -0.053 -8.242 1.00 1.00 OATOM 1697 CB LEU A1082 -15.143 -2.463 -8.695 1.00 1.00 CATOM 1698 CG LEU A1082 -13.786 -3.220 -8.647 1.00 1.00 CATOM 1699 CD1 LEU A1082 -13.527 -3.801 -7.229 1.00 1.00 CATOM 1700 CD2 LEU A1082 -13.707 -4.324 -9.760 1.00 1.00 CATOM 1701 HA LEU A1082 -15.479 -1.967 -6.595 1.00 1.00 HATOM 1702 HB1 LEU A1082 -15.184 -1.967 -9.666 1.00 1.00 HATOM 1703 HB2 LEU A1082 -15.980 -3.250 -8.697 1.00 1.00 HATOM 1704 HG LEU A1082 -13.011 -2.502 -8.889 1.00 1.00 H
ATOM 1705 HD21 LEU A1082 -14.460 -5.095 -9.520 1.00 1.00HATOM 1706 HD22 LEU A1082 -13.856 -3.903 -10.740 1.00 1.00HATOM 1707 HD23 LEU A1082 -12.681 -4.749 -9.767 1.00 1.00HATOM 1708 HD11 LEU A1082 -12.549 -4.266 -7.278 1.00 1.00HATOM 1709 HD12 LEU A1082 -13.499 -3.068 -6.477 1.00 1.00HATOM 1710 HD13 LEU A1082 -14.277 -4.586 -6.926 1.00 1.00HATOM 1711 HN LEU A1082 -16.332 0.056 -8.714 1.00 1.00HATOM 1712 NASP A1083 -13.593 -0.411 -5.990 1.00 1.00NATOM 1713 CA ASP A1083 -12.300 0.283 -5.667 1.00 1.00CATOM 1714 CASP A1083 -11.242 -0.765 -5.825 1.00 1.00CATOM 1715 OASP A1083 -11.321 -1.749 -5.077 1.00 1.00OATOM 1716 CB ASP A1083 -12.082 0.955 -4.254 1.00 1.00CATOM 1717 CG ASP A1083 -10.967 2.021 -3.992 1.00 1.00CATOM 1718 OD1 ASP A1083 -11.119 3.207 -4.265 1.00 1.00OATOM 1719 OD2 ASP A1083 -9.895 1.695 -3.449 1.00 1.00OATOM 1720 HA ASP A1083 -12.198 1.111 -6.349 1.00 1.00HATOM 1721 HB1 ASP A1083 -11.824 0.173 -3.539 1.00 1.00HATOM 1722 HB2 ASP A1083 -13.092 1.419 -3.958 1.00 1.00HATOM 1723 HN ASP A1083 -14.107 -0.766 -5.247 1.00 1.00HATOM 1724 NVAL A1084 -10.275 -0.590 -6.737 1.00 1.00NATOM 1725 CA VAL A1084 -9.274 -1.609 -7.015 1.00 1.00CATOM 1726 CVAL A1084 -8.045 -1.410 -6.141 1.00 1.00CATOM 1727 OVAL A1084 -7.072 -0.882 -6.608 1.00 1.00OATOM 1728 CB VAL A1084 -8.936 -1.573 -8.549 1.00 1.00CATOM 1729 CG1 VAL A1084 -7.887 -2.600 -8.987 1.00 1.00CATOM 1730 CG2 VAL A1084 -10.222 -1.659 -9.421 1.00 1.00CATOM 1731 HA VAL A1084 -9.709 -2.579 -6.791 1.00 1.00HATOM 1732 HB VAL A1084 -8.517 -0.538 -8.771 1.00 1.00HATOM 1733 HG11 VAL A1084 -8.249 -3.635 -8.833 1.00 1.00HATOM 1734 HG12 VAL A1084 -7.696 -2.555 -10.060 1.00 1.00HATOM 1735 HG13 VAL A1084 -6.944 -2.430 -8.436 1.00 1.00HATOM 1736 HG21 VAL A1084 -10.992 -0.922 -9.120 1.00 1.00HATOM 1737 HG22 VAL A1084 -9.953 -1.491 -10.505 1.00 1.00HATOM 1738 HG23 VAL A1084 -10.637 -2.705 -9.367 1.00 1.00HATOM 1739 HN VAL A1084 -10.181 0.333 -7.157 1.00 1.00HATOM 1740 NSER A1085 -8.056 -1.897 -4.895 1.00 1.00NATOM 1741 CA SER A1085 -6.850 -1.786 -4.026 1.00 1.00CATOM 1742 CSER A1085 -5.691 -2.619 -4.539 1.00 1.00CATOM 1743 OSER A1085 -5.266 -3.599 -3.941 1.00 1.00OATOM 1744 CB SER A1085 -7.185 -2.342 -2.622 1.00 1.00CATOM 1745 OG SER A1085 -6.127 -2.078 -1.636 1.00 1.00OATOM 1746 HA SER A1085 -6.564 -0.698 -3.922 1.00 1.00HATOM 1747 HB1 SER A1085 -7.410 -3.430 -2.696 1.00 1.00HATOM 1748 HB2 SER A1085 -8.062 -1.796 -2.228 1.00 1.00HATOM 1749 HG SER A1085 -5.933 -1.130 -1.502 1.00 1.00HATOM 1750 HN SER A1085 -8.863 -2.359 -4.524 1.00 1.00HATOM 1751 NALA A1086 -5.034 -2.201 -5.641 1.00 1.00NATOM 1752 CA ALA A1086 -3.970 -2.958 -6.273 1.00 1.00CATOM 1753 CALA A1086 -2.993 -2.122 -7.107 1.00 1.00CATOM 1754 OALA A1086 -1.818 -2.246 -6.825 1.00 1.00OATOM 1755 CB ALA A1086 -4.431 -4.135 -7.198 1.00 1.00CATOM 1756 HA ALA A1086 -3.401 -3.374 -5.427 1.00 1.00H
ATOM 1757 HB1 ALA A1086 -3.508 -4.728 -7.471 1.00 1.00 HATOM 1758 HB2 ALA A1086 -5.062 -4.795 -6.561 1.00 1.00 HATOM 1759 HB3 ALA A1086 -4.971 -3.675 -8.059 1.00 1.00 HATOM 1760 HN ALA A1086 -5.434 -1.396 -6.140 1.00 1.00 HATOM 1761 N ALA A1087 -3.450 -1.371 -8.166 1.00 1.00 NATOM 1762 CA ALA A1087 -2.500 -0.721 -9.069 1.00 1.00 CATOM 1763 C ALA A1087 -1.439 0.009 -8.310 1.00 1.00 CATOM 1764 O ALA A1087 -0.266 -0.278 -8.550 1.00 1.00 OATOM 1765 CB ALA A1087 -3.196 0.299 -10.022 1.00 1.00 CATOM 1766 HA ALA A1087 -2.012 -1.539 -9.583 1.00 1.00 HATOM 1767 HB1 ALA A1087 -2.471 0.819 -10.662 1.00 1.00 HATOM 1768 HB2 ALA A1087 -3.858 -0.269 -10.686 1.00 1.00 HATOM 1769 HB3 ALA A1087 -3.736 1.076 -9.495 1.00 1.00 HATOM 1770 HN ALA A1087 -4.400 -1.282 -8.371 1.00 1.00 HATOM 1771 N PHE A1088 -1.822 0.946 -7.423 1.00 1.00 NATOM 1772 CA PHE A1088 -0.794 1.712 -6.728 1.00 1.00 CATOM 1773 C PHE A1088 -0.577 1.067 -5.338 1.00 1.00 CATOM 1774 O PHE A1088 -0.572 1.771 -4.350 1.00 1.00 OATOM 1775 CB PHE A1088 -1.168 3.159 -6.721 1.00 1.00 CATOM 1776 CG PHE A1088 -0.908 3.894 -8.028 1.00 1.00 CATOM 1777 CD1 PHE A1088 -0.468 3.296 -9.228 1.00 1.00 CATOM 1778 CD2 PHE A1088 -1.155 5.285 -8.039 1.00 1.00 CATOM 1779 CE1 PHE A1088 -0.344 4.098 -10.350 1.00 1.00 CATOM 1780 CE2 PHE A1088 -1.127 6.038 -9.197 1.00 1.00 CATOM 1781 CZ PHE A1088 -0.692 5.424 -10.383 1.00 1.00 CATOM 1782 HA PHE A1088 0.211 1.562 -7.138 1.00 1.00 HATOM 1783 H31 PHE A1088 -0.694 3.803 -5.977 1.00 1.00 HATOM 1784 HB2 PHE A1088 -2.279 3.262 -6.624 1.00 1.00 HATOM 1785 HD2 PHE A1088 -1.361 5.772 -7.131 1.00 1.00 HATOM 1786 HE2 PHE A1088 -1.383 7.100 -9.235 1.00 1.00 HATOM 1787 HZ PHE A1088 -0.559 6.029 -11.282 1.00 1.00 HATOM 1788 HE1 PHE A1088 0.127 3.540 -11.213 1.00 1.00 HATOM 1789 HD1 PHE A1088 -0.255 2.216 -9.266 1.00 1.00 HATOM 1790 HN PHE A1088 -2.755 1.120 -7.230 1.00 1.00 HATOM 1791 N TYR A1089 -0.392 -0.288 -5.189 1.00 1.00 NATOM 1792 CA TYR A1089 -0.274 -0.899 -3.881 1.00 1.00 CATOM 1793 C TYR A1089 0.364 -2.284 -3.802 1.00 1.00 CATOM 1794 O TYR A1089 1.383 -2.393 -3.174 1.00 1.00 OATOM 1795 CB TYR A1089 -1.723 -1.008 -3.286 1.00 1.00 CATOM 1796 CG TYR A1089 -1.868 -0.802 -1.770 1.00 1.00 CATOM 1797 CD1 TYR A1089 -2.927 -0.034 -1.288 1.00 1.00 CATOM 1798 CD2 TYR A1089 -0.955 -1.323 -0.809 1.00 1.00 CATOM 1799 CE1 TYR A1089 -3.138 0.223 0.076 1.00 1.00 CATOM 1800 CE2 TYR A1089 -1.141 -1.045 0.555 1.00 1.00 CATOM 1801 CZ TYR A1089 -2.223 -0.290 1.005 1.00 1.00 CATOM 1802 OH TYR A1089 -2.373 -0.075 2.401 1.00 1.00 OATOM 1803 HA TYR A1089 0.303 -0.285 -3.220 1.00 1.00 HATOM 1804 HB2 TYR A1089 -2.121 -2.000 -3.539 1.00 1.00 HATOM 1805 HB1 TYR A1089 -2.345 -0.279 -3.752 1.00 1.00 HATOM 1806 HD2 TYR A1089 -0.137 -1.916 -1.153 1.00 1.00 HATOM 1807 HE2 TYR A1089 -0.406 -1.427 1.249 1.00 1.00 HATOM 1808 HE1 TYR A1089 -3.987 0.775 0.407 1.00 1.00 H
ATOM 1809 HD1 TYR A1089 -3.627 0.416 -2.005 1.00 1.00 HATOM 1810 HH TYR A1089 -3.116 0.484 2.621 1.00 1.00 HATOM 1811 HN TYR A1089 -0.525 -0.866 -5.977 1.00 1.00 HATOM 1812 NHIS A1090 -0.245 -3.349 -4.386 1.00 1.00 NATOM 1813 CA HIS A1090 0.036 -4.745 -4.070 1.00 1.00 CATOM 1814 CHIS A1090 0.495 -5.617 -5.216 1.00 1.00 CATOM 1815 OHIS A1090 -0.143 -6.618 -5.506 1.00 1.00 OATOM 1816 CB HIS A1090 -1.261 -5.342 -3.421 1.00 1.00 CATOM 1817 CG HIS A1090 -1.261 -6.785 -3.060 1.00 1.00 CATOM 1818 ND1 HIS A1090 -0.421 -7.296 -2.197 1.00 1.00 NATOM 1819 CD2 HIS A1090 -2.073 -7.786 -3.493 1.00 1.00 CATOM 1820 CE1 HIS A1090 -0.693 -8.555 -1.987 1.00 1.00 CATOM 1821 NE2 HIS A1090 -1.632 -8.926 -2.733 1.00 1.00 NATOM 1822 HA HIS A1090 0.830 -4.840 -3.328 1.00 1.00 HATOM 1823 HB1 HIS A1090 -2.017 -5.260 -4.233 1.00 1.00 HATOM 1824 HB2 HIS A1090 -1.513 -4.675 -2.555 1.00 1.00 HATOM 1825 HD2 HIS A1090 -2.827 -7.607 -4.243 1.00 1.00 HATOM 1826 HE1 HIS A1090 -0.118 -9.168 -1.297 1.00 1.00 HATOM 1827 HD1 HIS A1090 0.316 -6.808 -1.678 1.00 1.00 HATOM 1828 HN HIS A1090 -0.962 -3.217 -5.056 1.00 1.00 HATOM 1829 NLEU A1091 1.650 -5.280 -5.850 1.00 1.00 NATOM 1830 CA LEU A1091 2.139 -6.088 -6.984 1.00 1.00 CATOM 1831 CLEU A1091 3.616 -6.430 -6.942 1.00 1.00 CATOM 1832 OLEU A1091 4.344 -5.673 -6.286 1.00 1.00 OATOM 1833 CB LEU A1091 1.830 -5.255 -8.251 1.00 1.00 CATOM 1834 CG LEU A1091 0.299 -5.235 -8.560 1.00 1.00 CATOM 1835 CD1 LEU A1091 -0.079 -4.065 -9.559 1.00 1.00 CATOM 1836 CD2 LEU A1091 -0.133 -6.621 -9.117 1.00 1.00 CATOM 1837 HA LEU A1091 1.687 -7.083 -6.966 1.00 1.00 HATOM 1838 HB1 LEU A1091 2.348 -5.650 -9.171 1.00 1.00 HATOM 1839 HB2 LEU A1091 2.217 -4.217 -8.066 1.00 1.00 HATOM 1840 HG LEU A1091 -0.322 -5.071 -7.639 1.00 1.00 HATOM 1841 HD21 LEU A1091 -0.073 -7.480 -8.458 1.00 1.00 HATOM 1842 HD22 LEU A1091 -1.154 -6.399 -9.445 1.00 1.00 HATOM 1843 HD23 LEU A1091 0.457 -6.827 -10.034 1.00 1.00 HATOM 1844 HD11 LEU A1091 0.496 -4.148 -10.520 1.00 1.00 HATOM 1845 HD12 LEU A1091 -1.144 -4.138 -9.783 1.00 1.00 HATOM 1846 HD13 LEU A1091 0.089 -3.060 -9.098 1.00 1.00 HATOM 1847 HN LEU A1091 2.232 -4.502 -5.500 1.00 1.00 HATOM 1848 NPRO A1092 4.163 -7.526 -7.537 1.00 1.00 NATOM 1849 CA PRO A1092 3.354 -8.517 -8.207 1.00 1.00 CATOM 1850 CPRO A1092 2.776 -9.467 -7.154 1.00 1.00 CATOM 1851 OPRO A1092 3.219 -9.371 -6.028 1.00 1.00 OATOM 1852 CB PRO A1092 4.460 -9.267 -8.973 1.00 1.00 CATOM 1853 CG PRO A1092 5.647 -9.210 -7.963 1.00 1.00 CATOM 1854 CD PRO A1092 5.580 -7.789 -7.427 1.00 1.00 CATOM 1855 HA PRO A1092 2.528 -8.128 -8.857 1.00 1.00 HATOM 1856 HD2 PRO A1092 5.832 -7.757 -6.342 1.00 1.00 HATOM 1857 HD1 PRO A1092 6.178 -7.180 -8.092 1.00 1.00 HATOM 1858 HG2 PRO A1092 6.599 -9.413 -8.457 1.00 1.00 HATOM 1859 HG1 PRO A1092 5.491 -10.031 -7.206 1.00 1.00 HATOM 1860 HB1 PRO A1092 4.725 -8.743 -9.905 1.00 1.00 H
ATOM 1861 HB2 PRO A10924.199 -10.301 -9.271 1.00 1.00 HATOM 1862 NLEU A10931.854 -10.428 -7.421 1.00 1.00 NATOM 1863 CA LEU A10931.576 -11.535 -6.460 1.00 1.00 CATOM 1864 CLEU A10932.711 -12.545 -6.391 1.00 1.00 CATOM 1865 OLEU A10932.555 -13.721 -6.661 1.00 1.00 OATOM 1866 CB LEU A10931.015 -11.068 -5.067 1.00 1.00 CATOM 1867 CG LEU A10930.654 -12.292 -4.168 1.00 1.00 CATOM 1868 CD1 LEU A10930.544 -11.938 -2.648 1.00 1.00 CATOM 1869 CD2 LEU A1093 -0.666 -12.993 -4.524 1.00 1.00 CATOM 1870 HA LEU A10930.691 -12.037 -6.939 1.00 1.00 HATOM 1871 HB1 LEU A10930.122 -10.396 -5.129 1.00 1.00 HATOM 1872 HB2 LEU A10931.855 -10.516 -4.546 1.00 1.00 HATOM 1873 HG LEU A10931.492 -13.012 -4.182 1.00 1.00 HATOM 1874 HD21 LEU A1093 -1.561 -12.336 -4.542 1.00 1.00 HATOM 1875 HD22 LEU A1093 -0.580 -13.503 -5.539 1.00 1.00 HATOM 1876 HD23 LEU A1093 -0.845 -13.812 -3.857 1.00 1.00 HATOM 1877 HD11 LEU A10931.501 -11.650 -2.236 1.00 1.00 HATOM 1878 HD12 LEU A1093 -0.173 -11.132 -2.450 1.00 1.00 HATOM 1879 HD13 LEU A10930.286 -12.792 -2.071 1.00 1.00 HATOM 1880 HN LEU A10931.401 -10.426 -8.266 1.00 1.00 HATOM 1881 NHIS A10943.958 -12.140 -5.941 1.00 1.00 NATOM 1882 CA HIS A10945.150 -13.032 -5.808 1.00 1.00 CATOM 1883 CHIS A10946.114 -12.377 -4.787 1.00 1.00 CATOM 1884 OHIS A10945.943 -11.231 -4.382 1.00 1.00 OATOM 1885 CB HIS A10945.843 -13.047 -7.215 1.00 1.00 CATOM 1886 CG HIS A10945.770 -14.403 -7.842 1.00 1.00 CATOM 1887 ND1 HIS A10944.678 -15.116 -7.931 1.00 1.00 NATOM 1888 CD2 HIS A10946.798 -15.099 -8.386 1.00 1.00 CATOM 1889 CE1 HIS A10944.914 -16.253 -8.498 1.00 1.00 CATOM 1890 NE2 HIS A10946.127 -16.315 -8.758 1.00 1.00 NATOM 1891 HA HIS A10944.865 -14.054 -5.456 1.00 1.00 HATOM 1892 HB1 HIS A10946.862 -12.641 -7.126 1.00 1.00 HATOM 1893 HB2 HIS A10945.214 -12.421 -7.947 1.00 1.00 HATOM 1894 HD2 HIS A10947.888 -14.807 -8.478 1.00 1.00 HATOM 1895 HE1 HIS A10944.208 -17.033 -8.741 1.00 1.00 HATOM 1896 HD1 HIS A10943.776 -14.717 -7.645 1.00 1.00 HATOM 1897 HN HIS A10944.036 -11.130 -5.778 1.00 1.00 HATOM 1898 NPRO A10957.166 -13.095 -4.298 1.00 1.00 NATOM 1899 CA PRO A10958.168 -12.401 -3.496 1.00 1.00 CATOM 1900 CPRO A10958.949 -11.518 -4.465 1.00 1.00 CATOM 1901 OPRO A109510.075 -11.840 -4.828 1.00 1.00 OATOM 1902 CB PRO A10959.090 -13.609 -3.025 1.00 1.00 CATOM 1903 CG PRO A10958.823 -14.749 -4.054 1.00 1.00 CATOM 1904 CD PRO A10957.402 -14.492 -4.649 1.00 1.00 CATOM 1905 HA PRO A10957.772 -11.735 -2.693 1.00 1.00 HATOM 1906 HD2 PRO A10956.755 -15.160 -4.095 1.00 1.00 HATOM 1907 HD1 PRO A10957.489 -14.813 -5.720 1.00 1.00 HATOM 1908 HG2 PRO A10959.088 -15.792 -3.769 1.00 1.00 HATOM 1909 HG1 PRO A10959.530 -14.431 -4.828 1.00 1.00 HATOM 1910 HB1 PRO A10958.715 -13.957 -2.046 1.00 1.00 HATOM 1911 HB2 PRO A109510.120 -13.316 -2.847 1.00 1.00 HATOM 1912 NALA A10968.348 -10.386 -4.929 1.00 1.00 N
ATOM 1913 CA ALA A1096 9.193 -9.454 -5.715 1.00 1.00CATOM 1914 C ALA A1096 8.524 -8.133 -5.936 1.00 1.00CATOM 1915 O ALA A1096 8.643 -7.596 -7.005 1.00 1.00OATOM 1916 CB ALA A1096 9.412 -10.166 -7.068 1.00 1.00CATOM 1917 HA ALA A1096 10.107 -9.169 -5.198 1.00 1.00HATOM 1918 HB1 ALA A1096 9.896 -9.528 -7.790 1.00 1.00HATOM 1919 HB2 ALA A1096 10.054 -11.099 -7.029 1.00 1.00HATOM 1920 HB3 ALA A1096 8.367 -10.398 -7.377 1.00 1.00HATOM 1921 HN ALA A1096 7.416 -10.166 -4.670 1.00 1.00HATOM 1922 N ALA A1097 7.941 -7.531 -4.899 1.00 1.00NATOM 1923 CA ALA A1097 7.477 -6.130 -5.084 1.00 1.00CATOM 1924 C ALA A1097 8.756 -5.383 -4.881 1.00 1.00CATOM 1925 O ALA A1097 8.986 -4.961 -3.734 1.00 1.00OATOM 1926 CB ALA A1097 6.395 -5.751 -4.057 1.00 1.00CATOM 1927 HA ALA A1097 7.158 -5.902 -6.122 1.00 1.00HATOM 1928 HB1 ALA A1097 6.000 -4.713 -4.125 1.00 1.00HATOM 1929 HB2 ALA A1097 5.566 -6.449 -4.097 1.00 1.00HATOM 1930 HB3 ALA A1097 6.761 -5.823 -2.990 1.00 1.00HATOM 1931 HN ALA A1097 7.984 -7.895 -3.955 1.00 1.00HATOM 1932 N MET A1098 9.590 -5.193 -5.898 1.00 1.00NATOM 1933 CA MET A1098 10.943 -4.773 -5.549 1.00 1.00CATOM 1934 C MET A1098 11.757 -4.353 -6.768 1.00 1.00CATOM 1935 O MET A1098 12.161 -3.222 -6.640 1.00 1.00OATOM 1936 CB MET A1098 11.620 -5.915 -4.732 1.00 1.00CATOM 1937 CG MET A1098 13.096 -5.667 -4.462 1.00 1.00CATOM 1938 SD MET A1098 14.114 -5.995 -5.888 1.00 1.00SATOM 1939 CE MET A1098 15.724 -5.816 -5.040 1.00 1.00CATOM 1940 HA MET A1098 10.829 -3.853 -4.943 1.00 1.00HATOM 1941 HB1 MET A1098 11.496 -6.913 -5.180 1.00 1.00HATOM 1942 HB2 MET A1098 11.141 -5.917 -3.750 1.00 1.00HATOM 1943 HG1 MET A1098 13.220 -4.645 -4.134 1.00 1.00HATOM 1944 HG2 MET A1098 13.429 -6.338 -3.646 1.00 1.00HATOM 1945 HE1 MET A1098 15.839 -6.469 -4.193 1.00 1.00HATOM 1946 HE2 MET A1098 16.497 -6.028 -5.750 1.00 1.00HATOM 1947 HE3 MET A1098 15.787 -4.777 -4.598 1.00 1.00HATOM 1948 HN MET A1098 9.324 -5.528 -6.797 1.00 1.00HATOM 1949 N PRO A1099 12.078 -5.082 -7.918 1.00 1.00NATOM 1950 CA PRO A1099 12.964 4.480 -8.869 1.00 1.00CATOM 1951 C PRO A1099 12.765 -3.045 -9.345 1.00 1.00CATOM 1952 O PRO A1099 13.725 -2.269 -9.201 1.00 1.00OATOM 1953 CB PRO A1099 12.933 -5.559 -9.984 1.00 1.00CATOM 1954 CG PRO A1099 12.548 -6.909 -9.282 1.00 1.00CATOM 1955 CD PRO A1099 11.563 -6.436 -8.190 1.00 1.00CATOM 1956 HA PRO A1099 13.955 -4.462 -8.331 1.00 1.00HATOM 1957 HD2 PRO A1099 10.569 -6.455 -8.620 1.00 1.00HATOM 1958 HD1 PRO A1099 11.625 -7.213 -7.388 1.00 1.00HATOM 1959 HG2 PRO A1099 13.435 -7.364 -8.825 1.00 1.00HATOM 1960 HG1 PRO A1099 12.126 -7.633 -9.994 1.00 1.00HATOM 1961 HB1 PRO A1099 12.188 -5.404 -10.766 1.00 1.00HATOM 1962 HB2 PRO A1099 13.860 -5.613 -10.533 1.00 1.00HATOM 1963 N HIS A1100 11.613 -2.563 -9.875 1.00 1.00NATOM 1964 CA HIS A1100 10.370 -3.347 -10.064 1.00 1.00C
ATOM 1965 CHIS A1100 10.313 -3.602 -11.518 1.00 1.00CATOM 1966 OHIS A1100 10.715 -2.796 -12.332 1.00 1.00OATOM 1967 CB HIS A1100 9.130 -2.485 -9.611 1.00 1.00CATOM 1968 CG HIS A1100 7.828 -3.147 -9.907 1.00 1.00CATOM 1969 ND1 HIS A1100 7.276 -4.121 -9.235 1.00 1.00NATOM 1970 CD2 HIS A1100 6.995 -2.806 -10.896 1.00 1.00CATOM 1971 CE1 HIS A1100 6.115 -4.425 -9.738 1.00 1.00CATOM 1972 NE2 HIS A1100 5.876 -3.721 -10.753 1.00 1.00NATOM 1973 HA HIS A1100 10.301 -4.270 -9.498 1.00 1.00HATOM 1974 HB1 HIS A1100 9.022 -1.488 -10.110 1.00 1.00HATOM 1975 HB2 HIS A1100 9.274 -2.271 -8.529 1.00 1.00HATOM 1976 HD2 HIS A1100 7.198 -2.024 -11.608 1.00 1.00HATOM 1977 HE1 HIS A1100 5.403 -5.126 -9.381 1.00 1.00HATOM 1978 HD1 HIS A1100 7.646 -4.498 -8.335 1.00 1.00HATOM 1979 HN HIS A1100 11.669 -1.604 -10.247 1.00 1.00HATOM 1980 NLEU A1101 9.803 -4.799 -11.966 1.00 1.00NATOM 1981 CA LEU A1101 9.774 -5.140 -13.423 1.00 1.00CATOM 1982 CLEU A1101 8.608 -6.009 -13.780 1.00 1.00CATOM 1983 OLEU A1101 8.877 -7.053 -14.342 1.00 1.00OATOM 1984 CB LEU A1101 11.194 -5.679 -13.669 1.00 1.00CATOM 1985 CG LEU A1101 11.562 -6.050 -15.134 1.00 1.00CATOM 1986 CD1 LEU A1101 11.631 -4.733 -15.996 1.00 1.00CATOM 1987 CD2 LEU A1101 12.999 -6.668 -15.146 1.00 1.00CATOM 1988 HA LEU A1101 9.683 -4.231 -14.079 1.00 1.00HATOM 1989 HB1 LEU A1101 11.381 -6.545 -12.971 1.00 1.00HATOM 1990 HB2 LEU A1101 11.926 -4.942 -13.286 1.00 1.00HATOM 1991 HG LEU A1101 10.849 -6.784 -15.543 1.00 1.00HATOM 1992 HD21 LEU A1101 13.729 -6.052 -14.526 1.00 1.00HATOM 1993 HD22 LEU A1101 12.896 -7.666 -14.661 1.00 1.00HATOM 1994 HD23 LEU A1101 13.429 -6.768 -16.191 1.00 1.00HATOM 1995 HD11 LEU A1101 10.673 -4.215 -16.025 1.00 1.00HATOM 1996 HD12 LEU A1101 12.368 -4.046 -15.550 1.00 1.00HATOM 1997 HD13 LEU A1101 11.848 -4.956 -17.020 1.00 1.00HATOM 1998 HN LEU A1101 9.601 -5.577 -11.415 1.00 1.00HATOM 1999 NLEU A1102 7.373 -5.552 -13.390 1.00 1.00NATOM 2000 CA LEU A1102 6.202 -6.364 -13.741 1.00 1.00CATOM 2001 CLEU A1102 5.805 -6.124 -15.209 1.00 1.00CATOM 2002 OLEU A1102 5.408 -4.991 -15.419 1.00 1.00OATOM 2003 CB LEU A1102 4.997 -5.992 -12.804 1.00 1.00CATOM 2004 CG LEU A1102 3.655 -6.723 -13.169 1.00 1.00CATOM 2005 CD1 LEU A1102 3.715 -8.290 -13.243 1.00 1.00CATOM 2006 CD2 LEU A1102 2.570 -6.309 -12.150 1.00 1.00CATOM 2007 HA LEU A1102 6.469 -7.426 -13.627 1.00 1.00HATOM 2008 HB1 LEU A1102 4.865 -4.886 -12.897 1.00 1.00HATOM 2009 HB2 LEU A1102 5.326 -6.317 -11.819 1.00 1.00HATOM 2010 HG LEU A1102 3.306 -6.365 -14.186 1.00 1.00HATOM 2011 HD21 LEU A1102 2.846 -6.751 -11.166 1.00 1.00HATOM 2012 HD22 LEU A1102 2.527 -5.210 -12.093 1.00 1.00HATOM 2013 HD23 LEU A1102 1.599 -6.753 -12.410 1.00 1.00HATOM 2014 HD11 LEU A1102 2.830 -8.690 -13.775 1.00 1.00HATOM 2015 HD12 LEU A1102 4.592 -8.547 -13.880 1.00 1.00HATOM 2016 HD13 LEU A1102 3.878 -8.818 -12.305 1.00 1.00H
ATOM 2017 HN LEU A1102 7.327 -4.708 -12.845 1.00 1.00 HATOM 2018 NVAL A1103 5.893 -7.139 -16.130 1.00 1.00 NATOM 2019 CA VAL A1103 5.352 -6.960 -17.468 1.00 1.00 CATOM 2020 CVAL A1103 4.650 -8.238 -17.904 1.00 1.00 CATOM 2021 OVAL A1103 5.362 -9.265 -17.842 1.00 1.00 OATOM 2022 CB VAL A1103 6.441 -6.547 -18.503 1.00 1.00 CATOM 2023 CG1 VAL A1103 7.538 -5.652 -17.852 1.00 1.00 CATOM 2024 CG2 VAL A1103 5.828 -5.807 -19.745 1.00 1.00 CATOM 2025 HA VAL A1103 4.640 -6.127 -17.468 1.00 1.00 HATOM 2026 HB VAL A1103 7.007 -7.448 -18.815 1.00 1.00 HATOM 2027 HG11 VAL A1103 8.044 -6.139 -16.994 1.00 1.00 HATOM 2028 HG12 VAL A1103 8.345 -5.577 -18.662 1.00 1.00 HATOM 2029 HG13 VAL A1103 7.202 -4.633 -17.574 1.00 1.00 HATOM 2030 HG21 VAL A1103 5.518 -4.791 -19.489 1.00 1.00 HATOM 2031 HG22 VAL A1103 6.579 -5.695 -20.499 1.00 1.00 HATOM 2032 HG23 VAL A1103 4.967 -6.347 -20.143 1.00 1.00 HATOM 2033 HN VAL A1103 6.308 -8.016 -15.894 1.00 1.00 HATOM 2034 NGLY A1104 3.316 -8.171 -18.274 1.00 1.00 NATOM 2035 CA GLY A1104 2.623 -9.405 -18.555 1.00 1.00 CATOM 2036 CGLY A1104 1.494 -9.336 -19.560 1.00 1.00 CATOM 2037 OGLY A1104 1.287 -8.270 -20.132 1.00 1.00 OATOM 2038 HA2 GLY A1104 2.108 -9.666 -17.612 1.00 1.00 HATOM 2039 HA1 GLY A1104 3.350 -10.202 -18.649 1.00 1.00 HATOM 2040 HN GLY A1104 2.811 -7.350 -18.379 1.00 1.00 HATOM 2041 NSER A1105 0.740 -10.471 -19.715 1.00 1.00 NATOM 2042 CA SER A1105 -0.428 -10.562 -20.573 1.00 1.00 CATOM 2043 CSER A1105 -0.081 -11.052 -21.934 1.00 1.00 CATOM 2044 OSER A1105 0.900 -10.626 -22.551 1.00 1.00 OATOM 2045 CB SER A1105 -1.165 -9.239 -20.825 1.00 1.00 CATOM 2046 OG SER A1105 -2.512 -9.361 -21.310 1.00 1.00 OATOM 2047 HA SER A1105 -1.161 -11.250 -20.130 1.00 1.00 HATOM 2048 HB1 SER A1105 -0.675 -8.574 -21.603 1.00 1.00 HATOM 2049 HB2 SER A1105 -1.138 -8.677 -19.920 1.00 1.00 HATOM 2050 HG SER A1105 -3.048 -9.856 -20.708 1.00 1.00 HATOM 2051 HN SER A1105 0.947 -11.329 -19.170 1.00 1.00 HATOM 2052 NSER A1106 -0.906 -11.991 -22.459 1.00 1.00 NATOM 2053 CA SER A1106 -0.613 -12.527 -23.801 1.00 1.00 CATOM 2054 CSER A1106 0.755 -13.156 -23.889 1.00 1.00 CATOM 2055 OSER A1106 1.721 -12.531 -24.311 1.00 1.00 OATOM 2056 CB SER A1106 -0.811 -11.453 -24.904 1.00 1.00 CATOM 2057 OG SER A1106 -0.531 -11.976 -26.238 1.00 1.00 OATOM 2058 HA SER A1106 -1.293 -13.330 -24.064 1.00 1.00 HATOM 2059 HB1 SER A1106 -0.206 -10.577 -24.705 1.00 1.00 HATOM 2060 HB2 SER A1106 -1.882 -11.053 -24.886 1.00 1.00 HATOM 2061 HG SER A1106 0.399 -11.980 -26.374 1.00 1.00 HATOM 2062 HN SER A1106 -1.677 -12.383 -21.914 1.00 1.00 HATOM 2063 NGLY A1107 0.834 -14.467 -23.457 1.00 1.00 NATOM 2064 CA GLY A1107 2.148 -15.200 -23.460 1.00 1.00 CATOM 2065 CGLY A1107 2.868 -15.166 -22.152 1.00 1.00 CATOM 2066 OGLY A1107 3.780 -14.350 -22.076 1.00 1.00 OATOM 2067 HA2 GLY A1107 2.893 -14.810 -24.169 1.00 1.00 HATOM 2068 HA1 GLY A1107 1.921 -16.239 -23.777 1.00 1.00 H
ATOM 2069 HN GLY A1107-0.009 -14.964 -23.187 1.00 1.00 HATOM 2070 NLEU A1108 2.642 -16.087 -21.177 1.00 1.00 NATOM 2071 CA LEU A1108 3.579 -16.164 -20.056 1.00 1.00 CATOM 2072 CLEU A1108 5.018 -16.420 -20.504 1.00 1.00 CATOM 2073 OLEU A1108 5.920 -15.749 -20.009 1.00 1.00 OATOM 2074 CB LEU A1108 3.175 -17.126 -18.938 1.00 1.00 CATOM 2075 CG LEU A1108 4.178 -17.250 -17.744 1.00 1.00 CATOM 2076 CD1 LEU A1108 4.582 -15.938 -17.124 1.00 1.00 CATOM 2077 CD2 LEU A1108 3.647 -18.262 -16.639 1.00 1.00 CATOM 2078 HA LEU A1108 3.584 -15.177 -19.627 1.00 1.00 HATOM 2079 HB1 LEU A1108 2.939 -18.151 -19.405 1.00 1.00 HATOM 2080 HB2 LEU A1108 2.171 -16.868 -18.569 1.00 1.00 HATOM 2081 HG LEU A1108 5.082 -17.775 -18.188 1.00 1.00 HATOM 2082 HD21 LEU A1108 4.419 -18.534 -15.870 1.00 1.00 HATOM 2083 HD22 LEU A1108 3.337 -19.173 -17.105 1.00 1.00 HATOM 2084 HD23 LEU A1108 2.773 -17.777 -16.140 1.00 1.00 HATOM 2085 HD11 LEU A1108 5.218 -15.347 -17.732 1.00 1.00 HATOM 2086 HD12 LEU A1108 5.079 -16.095 -16.169 1.00 1.00 HATOM 2087 HD13 LEU A1108 3.606 -15.346 -17.011 1.00 1.00 HATOM 2088 HN LEU A1108 1.880 -16.708 -21.231 1.00 1.00 HATOM 2089 NSER A1109 5.179 -17.447 -21.378 1.00 1.00 NATOM 2090 CA SER A1109 6.501 -17.943 -21.779 1.00 1.00 CATOM 2091 CSER A1109 7.471 -16.769 -22.032 1.00 1.00 CATOM 2092 OSER A1109 8.529 -16.663 -21.417 1.00 1.00 OATOM 2093 CB SER A1109 6.448 -18.887 -23.032 1.00 1.00 CATOM 2094 OG SER A1109 5.855 -18.239 -24.245 1.00 1.00 OATOM 2095 HA SER A1109 6.871 -18.496 -20.883 1.00 1.00 HATOM 2096 H31 SER A1109 5.883 -19.834 -22.877 1.00 1.00 HATOM 2097 HB2 SER A1109 7.516 -19.105 -23.232 1.00 1.00 HATOM 2098 HG SER A1109 4.902 -18.129 -24.201 1.00 1.00 HATOM 2099 HN SER A1109 4.389 -17.950 -21.734 1.00 1.00 HATOM 2100 NARG A1110 7.044 -15.860 -22.938 1.00 1.00 NATOM 2101 CA ARG A1110 7.995 -14.781 -23.302 1.00 1.00 CATOM 2102 CARG A1110 8.407 -13.958 -22.095 1.00 1.00 CATOM 2103 OARG A1110 9.516 -13.495 -22.030 1.00 1.00 OATOM 2104 CB ARG A1110 7.449 -13.889 -24.446 1.00 1.00 CATOM 2105 CG ARG A1110 6.230 -13.004 -23.921 1.00 1.00 CATOM 2106 CD ARG A1110 5.392 -12.497 -25.161 1.00 1.00 CATOM 2107 NE ARG A1110 4.170 -11.868 -24.603 1.00 1.00 NATOM 2108 CZ ARG A1110 4.093 -10.624 -24.167 1.00 1.00 CATOM 2109 NH1 ARG A1110 5.108 -9.796 -24.145 1.00 1.00 NATOM 2110 NH2 ARG A1110 2.909 -10.249 -23.737 1.00 1.00 NATOM 2111 HA ARG A1110 8.906 -15.239 -23.622 1.00 1.00 HATOM 2112 HB1 ARG A1110 7.101 -14.509 -25.280 1.00 1.00 HATOM 2113 HB2 ARG A1110 8.292 -13.240 -24.783 1.00 1.00 HATOM 2114 HG1 ARG A1110 6.660 -12.177 -23.272 1.00 1.00 HATOM 2115 HG2 ARG A1110 5.619 -13.682 -23.244 1.00 1.00 HATOM 2116 HD1 ARG A1110 5.078 -13.396 -25.651 1.00 1.00 HATOM 2117 HD2 ARG A1110 6.059 -11.951 -25.810 1.00 1.00 HATOM 2118 HE ARG A1110 3.317 -12.385 -24.612 1.00 1.00 HATOM 2119 HH12 ARG A1110 5.000 -8.791 -23.750 1.00 1.00 HATOM 2120 HH11 ARG A1110 6.015 -10.113 -24.453 1.00 1.00 H
ATOM 2121 HH22 ARG A1110 2.759 -9.310 -23.318 1.00 1.00 HATOM 2122 HH21 ARG A1110 2.046 -10.875 -23.741 1.00 1.00 HATOM 2123 HN ARG A1110 6.157 -15.980 -23.374 1.00 1.00 HATOM 2124 NTYR A1111 7.555 -13.748 -21.089 1.00 1.00 NATOM 2125 CA TYR A1111 8.038 -13.153 -19.828 1.00 1.00 CATOM 2126 CTYR A1111 9.068 -13.981 -19.133 1.00 1.00 CATOM 2127 OTYR A1111 10.226 -13.596 -19.009 1.00 1.00 OATOM 2128 CB TYR A1111 6.902 -12.605 -18.931 1.00 1.00 CATOM 2129 CG TYR A1111 6.056 -11.608 -19.776 1.00 1.00 CATOM 2130 CD1 TYR A1111 6.563 -10.342 -20.080 1.00 1.00 CATOM 2131 CD2 TYR A1111 4.821 -11.960 -20.304 1.00 1.00 CATOM 2132 CE1 TYR A1111 5.824 -9.389 -20.773 1.00 1.00 CATOM 2133 CE2 TYR A1111 4.081 -11.041 -21.058 1.00 1.00 CATOM 2134 CZ TYR A1111 4.529 -9.704 -21.240 1.00 1.00 CATOM 2135 OH TYR A1111 3.712 -8.761 -21.876 1.00 1.00 OATOM 2136 HA TYR A1111 8.570 -12.216 -20.191 1.00 1.00 HATOM 2137 HB2 TYR A1111 7.301 -12.047 -18.068 1.00 1.00 HATOM 2138 HB1 TYR A1111 6.309 -13.431 -18.521 1.00 1.00 HATOM 2139 HD2 TYR A1111 4.470 -12.940 -20.140 1.00 1.00 HATOM 2140 HE2 TYR A1111 3.096 -11.327 -21.427 1.00 1.00 HATOM 2141 HE1 TYR A1111 6.315 -8.402 -21.048 1.00 1.00 HATOM 2142 HD1 TYR A1111 7.540 -10.111 -19.709 1.00 1.00 HATOM 2143 HH TYR A1111 3.720 -7.931 -21.402 1.00 1.00 HATOM 2144 HN TYR A1111 6.628 -14.092 -21.066 1.00 1.00 HATOM 2145 NVAL A1112 8.701 -15.177 -18.611 1.00 1.00 NATOM 2146 CA VAL A1112 9.717 -16.020 -17.993 1.00 1.00 CATOM 2147 CVAL A1112 10.992 -16.104 -18.848 1.00 1.00 CATOM 2148 OVAL A1112 12.054 -15.999 -18.248 1.00 1.00 OATOM 2149 CB VAL A1112 9.156 -17.435 -17.801 1.00 1.00 CATOM 2150 CG1 VAL A1112 10.312 -18.429 -17.378 1.00 1.00 CATOM 2151 CG2 VAL A1112 8.123 -17.507 -16.676 1.00 1.00 CATOM 2152 HA VAL A1112 9.983 -15.510 -17.031 1.00 1.00 HATOM 2153 HB VAL A1112 8.577 -17.756 -18.683 1.00 1.00 HATOM 2154 HG11 VAL A1112 10.849 -18.082 -16.535 1.00 1.00 HATOM 2155 HG12 VAL A1112 11.105 -18.560 -18.128 1.00 1.00 HATOM 2156 HG13 VAL A1112 9.874 -19.444 -17.214 1.00 1.00 HATOM 2157 HG21 VAL A1112 7.722 -18.567 -16.569 1.00 1.00 HATOM 2158 HG22 VAL A1112 7.246 -16.837 -16.920 1.00 1.00 HATOM 2159 HG23 VAL A1112 8.465 -17.273 -15.675 1.00 1.00 HATOM 2160 HN VAL A1112 7.748 -15.499 -18.677 1.00 1.00 HATOM 2161 NALA A1113 10.940 -16.236 -20.181 1.00 1.00 NATOM 2162 CA ALA A1113 12.166 -16.325 -20.955 1.00 1.00 CATOM 2163 CALA A1113 12.860 -14.997 -20.871 1.00 1.00 CATOM 2164 OALA A1113 13.974 -14.960 -20.403 1.00 1.00 OATOM 2165 CB ALA A1113 11.911 -16.632 -22.443 1.00 1.00 CATOM 2166 HA ALA A1113 12.767 -17.170 -20.580 1.00 1.00 HATOM 2167 HB1 ALA A1113 11.445 -17.600 -22.574 1.00 1.00 HATOM 2168 HB2 ALA A1113 12.870 -16.646 -22.949 1.00 1.00 HATOM 2169 HB3 ALA A1113 11.323 -15.833 -22.943 1.00 1.00 HATOM 2170 HN ALA A1113 10.072 -16.239 -20.666 1.00 1.00 HATOM 2171 NARG A1114 12.182 -13.881 -21.263 1.00 1.00 NATOM 2172 CA ARG A1114 12.948 -12.614 -21.359 1.00 1.00 C
ATOM 2173 CARG A1114 12.991 -11.926 -19.975 1.00 1.00 CATOM 2174 OARG A1114 14.084 -11.545 -19.498 1.00 1.00 OATOM 2175 CB ARG A1114 12.330 -11.664 -22.424 1.00 1.00 CATOM 2176 CG ARG A1114 13.245 -10.492 -22.948 1.00 1.00 CATOM 2177 CD ARG A1114 13.471 -9.370 -21.889 1.00 1.00 CATOM 2178 NE ARG A1114 14.445 -9.687 -20.798 1.00 1.00 NATOM 2179 CZ ARG A1114 14.593 -8.958 -19.715 1.00 1.00 CATOM 2180 NH1 ARG A1114 13.880 -7.902 -19.485 1.00 1.00 NATOM 2181 NH2 ARG A1114 15.479 -9.307 -18.836 1.00 1.00 NATOM 2182 HA ARG A1114 13.973 -12.832 -21.666 1.00 1.00 HATOM 2183 HB1 ARG A1114 11.332 -11.238 -22.114 1.00 1.00 HATOM 2184 HB2 ARG A1114 12.140 -12.314 -23.314 1.00 1.00 HATOM 2185 HG1 ARG A1114 12.702 -10.056 -23.810 1.00 1.00 HATOM 2186 HG2 ARG A1114 14.204 -10.823 -23.358 1.00 1.00 HATOM 2187 HD1 ARG A1114 12.503 -9.216 -21.478 1.00 1.00 HATOM 2188 HD2 ARG A1114 13.802 -8.449 -22.363 1.00 1.00 HATOM 2189 HE ARG A1114 15.051 -10.516 -20.947 1.00 1.00 HATOM 2190 HH12 ARG A1114 14.015 -7.327 -18.666 1.00 1.00 HATOM 2191 HH11 ARG A1114 13.216 -7.533 -20.173 1.00 1.00 HATOM 2192 HH22 ARG A1114 15.676 -8.762 -17.943 1.00 1.00 HATOM 2193 HH21 ARG A1114 16.040 -10.167 -18.981 1.00 1.00 HATOM 2194 HN ARG A1114 11.119 -13.932 -21.488 1.00 1.00 HATOM 2195 NLEU A1115 11.821 -11.619 -19.393 1.00 1.00 NATOM 2196 CA LEU A1115 11.791 -10.973 -18.095 1.00 1.00 CATOM 2197 CLEU A1115 12.716 -11.707 -17.199 1.00 1.00 CATOM 2198 OLEU A1115 13.669 -11.099 -16.724 1.00 1.00 OATOM 2199 CB LEU A1115 10.307 -10.820 -17.573 1.00 1.00 CATOM 2200 CG LEU A1115 10.056 -9.883 -16.340 1.00 1.00 CATOM 2201 CD1 LEU A1115 8.559 -9.887 -15.942 1.00 1.00 CATOM 2202 CD2 LEU A1115 11.051 -10.146 -15.166 1.00 1.00 CATOM 2203 HA LEU A1115 12.199 -9.971 -18.211 1.00 1.00 HATOM 2204 HB1 LEU A1115 9.883 -11.795 -17.215 1.00 1.00 HATOM 2205 HB2 LEU A1115 9.681 -10.484 -18.410 1.00 1.00 HATOM 2206 HG LEU A1115 10.226 -8.888 -16.763 1.00 1.00 HATOM 2207 HD21 LEU A1115 10.956 -11.208 -14.821 1.00 1.00 HATOM 2208 HD22 LEU A1115 10.743 -9.426 -14.365 1.00 1.00 HATOM 2209 HD23 LEU A1115 12.070 -9.887 -15.549 1.00 1.00 HATOM 2210 HD11 LEU A1115 7.957 -9.575 -16.772 1.00 1.00 HATOM 2211 HD12 LEU A1115 8.386 -9.201 -15.147 1.00 1.00 HATOM 2212 HD13 LEU A1115 8.259 -10.863 -15.687 1.00 1.00 HATOM 2213 HN LEU A1115 10.953 -11.945 -19.801 1.00 1.00 HATOM 2214 NSER A1116 12.399 -12.986 -16.952 1.00 1.00 NATOM 2215 CA SER A1116 13.301 -13.796 -16.107 1.00 1.00 CATOM 2216 CSER A1116 13.378 -13.340 -14.652 1.00 1.00 CATOM 2217 OSER A1116 13.013 -14.133 -13.812 1.00 1.00 OATOM 2218 CB SER A1116 14.693 -13.945 -16.796 1.00 1.00 CATOM 2219 OG SER A1116 15.553 -14.621 -15.875 1.00 1.00 OATOM 2220 HA SER A1116 12.907 -14.783 -16.124 1.00 1.00 HATOM 2221 HB1 SER A1116 15.058 -12.965 -17.172 1.00 1.00 HATOM 2222 HB2 SER A1116 14.656 -14.554 -17.749 1.00 1.00 HATOM 2223 HG SER A1116 16.378 -14.895 -16.258 1.00 1.00 HATOM 2224 HN SER A1116 11.688 -13.529 -17.462 1.00 1.00 H
ATOM 2225 NSER A1117 13.875 -12.127 -14.340 1.00 1.00 NATOM 2226 CA SER A1117 14.086 -11.818 -12.916 1.00 1.00 CATOM 2227 CSER A1117 12.878 -12.071 -12.004 1.00 1.00 CATOM 2228 OSER A1117 11.768 -12.035 -12.498 1.00 1.00 OATOM 2229 CB SER A1117 14.374 -10.313 -12.747 1.00 1.00 CATOM 2230 OG SER A1117 15.665 -9.951 -13.181 1.00 1.00 OATOM 2231 HA SER A1117 14.964 -12.389 -12.607 1.00 1.00 HATOM 2232 HB1 SER A1117 14.480 -9.997 -11.698 1.00 1.00 HATOM 2233 HB2 SER A1117 13.572 -9.683 -13.183 1.00 1.00 HATOM 2234 HG SER A1117 15.864 -10.036 -14.098 1.00 1.00 HATOM 2235 HN SER A1117 14.194 -11.494 -15.029 1.00 1.00 HATOM 2236 NASN A1118 13.159 -12.257 -10.673 1.00 1.00 NATOM 2237 CA ASN A1118 12.121 -12.657 -9.756 1.00 1.00 CATOM 2238 CASN A1118 10.729 -12.067 -9.978 1.00 1.00 CATOM 2239 OASN A1118 9.806 -12.791 -9.646 1.00 1.00 OATOM 2240 CB ASN A1118 12.485 -12.443 -8.304 1.00 1.00 CATOM 2241 CG ASN A1118 12.656 -10.989 -7.978 1.00 1.00 CATOM 2242 OD1 ASN A1118 12.407 -10.138 -8.819 1.00 1.00 OATOM 2243 ND2 ASN A1118 13.114 -10.551 -6.763 1.00 1.00 NATOM 2244 HA ASN A1118 11.900 -13.683 -9.986 1.00 1.00 HATOM 2245 HB1 ASN A1118 13.392 -13.002 -8.069 1.00 1.00 HATOM 2246 HB2 ASN A1118 11.715 -12.824 -7.590 1.00 1.00 HATOM 2247 HD22 ASN A1118 13.219 -9.591 -6.655 1.00 1.00 HATOM 2248 HD21 ASN A1118 13.372 -11.224 -6.006 1.00 1.00 HATOM 2249 HN ASN A1118 14.136 -12.225 -10.365 1.00 1.00 HATOM 2250 NSER A1119 10.457 -10.877 -10.569 1.00 1.00 NATOM 2251 CA SER A1119 9.074 -10.434 -10.770 1.00 1.00 CATOM 2252 CSER A1119 8.265 -11.387 -11.632 1.00 1.00 CATOM 2253 OSER A1119 7.056 -11.316 -11.545 1.00 1.00 OATOM 2254 CB SER A1119 9.053 -9.048 -11.522 1.00 1.00 CATOM 2255 OG SER A1119 7.671 -8.656 -11.694 1.00 1.00 OATOM 2256 HA SER A1119 8.527 -10.322 -9.830 1.00 1.00 HATOM 2257 HB1 SER A1119 9.443 -9.205 -12.518 1.00 1.00 HATOM 2258 HB2 SER A1119 9.691 -8.258 -11.061 1.00 1.00 HATOM 2259 HG SER A1119 7.267 -8.499 -10.856 1.00 1.00 HATOM 2260 HN SER A1119 11.215 -10.305 -10.875 1.00 1.00 HATOM 2261 NARG A1120 8.865 -12.256 -12.515 1.00 1.00 NATOM 2262 CA ARG A1120 8.014 -13.116 -13.357 1.00 1.00 CATOM 2263 CARG A1120 6.892 -13.792 -12.624 1.00 1.00 CATOM 2264 OARG A1120 7.007 -14.146 -11.455 1.00 1.00 OATOM 2265 CB ARG A1120 8.854 -14.165 -14.136 1.00 1.00 CATOM 2266 CG ARG A1120 9.314 -15.449 -13.367 1.00 1.00 CATOM 2267 CD ARG A1120 10.091 -15.121 -12.033 1.00 1.00 CATOM 2268 NE ARG A1120 10.572 -16.404 -11.473 1.00 1.00 NATOM 2269 CZ ARG A1120 11.729 -16.974 -11.769 1.00 1.00 CATOM 2270 NH1 ARG A1120 12.566 -16.469 -12.619 1.00 1.00 NATOM 2271 NH2 ARG A1120 12.029 -18.057 -11.137 1.00 1.00 NATOM 2272 HA ARG A1120 7.641 -12.344 -14.041 1.00 1.00 HATOM 2273 HB1 ARG A1120 9.757 -13.615 -14.518 1.00 1.00 HATOM 2274 HB2 ARG A1120 8.277 -14.473 -15.047 1.00 1.00 HATOM 2275 HG1 ARG A1120 9.962 -16.051 -13.976 1.00 1.00 HATOM 2276 HG2 ARG A1120 8.393 -16.029 -13.193 1.00 1.00 H
ATOM 2277 HD1 ARG A1120 9.432 -14.680 -11.317 1.00 1.00HATOM 2278 HD2 ARG A1120 10.855 -14.342 -12.157 1.00 1.00HATOM 2279 HE ARG A1120 9.967 -16.856 -10.760 1.00 1.00HATOM 2280 HH12 ARG A1120 13.469 -16.899 -12.829 1.00 1.00HATOM 2281 HH11 ARG A1120 12.343 -15.631 -13.199 1.00 1.00HATOM 2282 HH22 ARG A1120 12.919 -18.532 -11.328 1.00 1.00HATOM 2283 HH21 ARG A1120 11.387 -18.547 -10.442 1.00 1.00HATOM 2284 HN ARG A1120 9.867 -12.216 -12.572 1.00 1.00HATOM 2285 NILE A1121 5.726 -13.981 -13.292 1.00 1.00NATOM 2286 CA ILE A1121 4.513 -14.349 -12.540 1.00 1.00CATOM 2287 CILE A1121 3.355 -14.670 -13.476 1.00 1.00CATOM 2288 OILE A1121 3.224 -13.933 -14.460 1.00 1.00OATOM 2289 CB ILE A1121 4.019 -13.329 -11.469 1.00 1.00CATOM 2290 CG1 ILE A1121 2.729 -13.813 -10.707 1.00 1.00CATOM 2291 CG2 ILE A1121 3.787 -11.999 -12.193 1.00 1.00CATOM 2292 CD1 ILE A1121 2.213 -12.810 -9.698 1.00 1.00CATOM 2293 HA ILE A1121 4.697 -15.317 -12.001 1.00 1.00HATOM 2294 HB ILE A1121 4.769 -13.174 -10.681 1.00 1.00HATOM 2295 HG11 ILE A1121 2.922 -14.841 -10.321 1.00 1.00HATOM 2296 HG12 ILE A1121 1.892 -13.887 -11.419 1.00 1.00HATOM 2297 HD11 ILE A1121 1.817 -11.934 -10.216 1.00 1.00HATOM 2298 HD12 ILE A1121 3.011 -12.583 -8.984 1.00 1.00HATOM 2299 HD13 ILE A1121 1.332 -13.183 -9.133 1.00 1.00HATOM 2300 HG21 ILE A1121 3.575 -11.166 -11.536 1.00 1.00HATOM 2301 HG22 ILE A1121 2.970 -12.028 -12.961 1.00 1.00HATOM 2302 HG23 ILE A1121 4.708 -11.723 -12.674 1.00 1.00HATOM 2303 HN ILE A1121 5.604 -13.713 -14.260 1.00 1.00HATOM 2304 NPHE A1122 2.523 -15.677 -13.227 1.00 1.00NATOM 2305 CA PHE A1122 1.317 -15.919 -14.087 1.00 1.00CATOM 2306 CPHE A1122 0.289 -14.817 -13.921 1.00 1.00CATOM 2307 OPHE A1122 -0.762 -15.093 -13.338 1.00 1.00OATOM 2308 CB PHE A1122 0.718 -17.315 -13.781 1.00 1.00CATOM 2309 CG PHE A1122 -0.476 -17.728 -14.695 1.00 1.00CATOM 2310 CD1 PHE A1122 -0.333 -17.850 -16.067 1.00 1.00CATOM 2311 CD2 PHE A1122 -1.730 -17.988 -14.133 1.00 1.00CATOM 2312 CE1 PHE A1122 -1.390 -18.311 -16.881 1.00 1.00CATOM 2313 CE2 PHE A1122 -2.824 -18.391 -14.913 1.00 1.00CATOM 2314 CZ PHE A1122 -2.625 -18.551 -16.279 1.00 1.00CATOM 2315 HA PHE A1122 1.591 -15.911 -15.178 1.00 1.00HATOM 2316 HB1 PHE A1122 0.420 -17.262 -12.718 1.00 1.00HATOM 2317 HB2 PHE A1122 1.473 -18.112 -13.905 1.00 1.00HATOM 2318 HD2 PHE A1122 -1.846 -17.893 -13.035 1.00 1.00HATOM 2319 HE2 PHE A1122 -3.833 -18.502 -14.510 1.00 1.00HATOM 2320 HZ PHE A1122 -3.448 -18.913 -16.874 1.00 1.00HATOM 2321 HE1 PHE A1122 -1.259 -18.447 -17.909 1.00 1.00HATOM 2322 HD1 PHE A1122 0.589 -17.613 -16.654 1.00 1.00HATOM 2323 HN PHE A1122 2.639 -16.283 -12.442 1.00 1.00HATOM 2324 NASN A1123 0.583 -13.611 -14.413 1.00 1.00NATOM 2325 CA ASN A1123 -0.403 -12.495 -14.218 1.00 1.00CATOM 2326 CASN A1123 -0.998 -11.957 -15.526 1.00 1.00CATOM 2327 OASN A1123 -0.263 -11.994 -16.515 1.00 1.00OATOM 2328 CB ASN A1123 0.145 -11.269 -13.429 1.00 1.00C
ATOM 2329 CG ASN A1123 -0.872 -10.367 -12.817 1.00 1.00CATOM 2330 OD1 ASN A1123 -2.037 -10.604 -12.887 1.00 1.00OATOM 2331 ND2 ASN A1123 -0.476 -9.222 -12.222 1.00 1.00NATOM 2332 HA ASN A1123 -1.280 -12.773 -13.584 1.00 1.00HATOM 2333 HB1 ASN A1123 0.904 -10.736 -14.032 1.00 1.00HATOM 2334 HB2 ASN A1123 0.641 -11.744 -12.616 1.00 1.00HATOM 2335 HD22 ASN A1123 -1.210 -8.547 -11.997 1.00 1.00HATOM 2336 HD21 ASN A1123 0.466 -8.978 -11.987 1.00 1.00HATOM 2337 HN ASN A1123 1.419 -13.479 -14.959 1.00 1.00HATOM 2338 NTYR A1124 -2.215 -11.410 -15.516 1.00 1.00NATOM 2339 CA TYR A1124 -2.912 -10.891 -16.737 1.00 1.00CATOM 2340 CTYR A1124 -2.972 -11.906 -17.875 1.00 1.00CATOM 2341 OTYR A1124 -3.485 -11.480 -18.900 1.00 1.00OATOM 2342 CB TYR A1124 -2.153 -9.635 -17.176 1.00 1.00CATOM 2343 CG TYR A1124 -1.938 -8.590 -16.088 1.00 1.00CATOM 2344 CD1 TYR A1124 -2.957 -8.112 -15.279 1.00 1.00CATOM 2345 CD2 TYR A1124 -0.662 -8.093 -15.817 1.00 1.00CATOM 2346 CE1 TYR A1124 -2.716 -7.111 -14.336 1.00 1.00CATOM 2347 CE2 TYR A1124 -0.357 -7.199 -14.777 1.00 1.00CATOM 2348 CZ TYR A1124 -1.424 -6.768 -13.947 1.00 1.00CATOM 2349 OH TYR A1124 -1.271 -5.956 -12.806 1.00 1.00OATOM 2350 HA TYR A1124 -3.956 -10.598 -16.581 1.00 1.00HATOM 2351 HB2 TYR A1124 -2.774 -9.118 -17.906 1.00 1.00HATOM 2352 HB1 TYR A1124 -1.221 -9.950 -17.650 1.00 1.00HATOM 2353 HD2 TYR A1124 0.108 -8.362 -16.535 1.00 1.00HATOM 2354 HE2 TYR A1124 0.633 -6.859 -14.657 1.00 1.00HATOM 2355 HE1 TYR A1124 -3.580 -6.578 -13.955 1.00 1.00HATOM 2356 HD1 TYR A1124 -3.978 -8.461 -15.384 1.00 1.00HATOM 2357 HH TYR A1124 -0.422 -5.564 -12.720 1.00 1.00HATOM 2358 HN TYR A1124 -2.621 -11.229 -14.643 1.00 1.00HATOM 2359 NGLN A1125 -2.555 -13.175 -17.808 1.00 1.00NATOM 2360 CA GLN A1125 -3.026 -14.086 -18.876 1.00 1.00CATOM 2361 CGLN A1125 -4.521 -14.185 -18.742 1.00 1.00CATOM 2362 OGLN A1125 -4.864 -14.867 -17.797 1.00 1.00OATOM 2363 CB GLN A1125 -2.379 -15.510 -18.785 1.00 1.00CATOM 2364 CG GLN A1125 -0.989 -15.592 -19.456 1.00 1.00CATOM 2365 CD GLN A1125 -0.138 -14.394 -19.061 1.00 1.00CATOM 2366 OE1 GLN A1125 0.283 -13.593 -19.875 1.00 1.00OATOM 2367 NE2 GLN A1125 0.132 -14.238 -17.773 1.00 1.00NATOM 2368 HA GLN A1125 -2.724 -13.610 -19.844 1.00 1.00HATOM 2369 HB1 GLN A1125 -3.026 -16.335 -19.150 1.00 1.00HATOM 2370 HB2 GLN A1125 -2.279 -15.746 -17.716 1.00 1.00HATOM 2371 HG1 GLN A1125 -1.051 -15.620 -20.552 1.00 1.00HATOM 2372 HG2 GLN A1125 -0.424 -16.454 -19.083 1.00 1.00HATOM 2373 HE22 GLN A1125 0.760 -13.504 -17.446 1.00 1.00HATOM 2374 HE21 GLN A1125 -0.122 -14.869 -17.072 1.00 1.00HATOM 2375 HN GLN A1125 -2.129 -13.513 -16.988 1.00 1.00HATOM 2376 NHIS A1126 -5.355 -13.533 -19.565 1.00 1.00NATOM 2377 CA HIS A1126 -6.765 -13.570 -19.303 1.00 1.00CATOM 2378 CHIS A1126 -7.556 -13.546 -20.569 1.00 1.00CATOM 2379 OHIS A1126 -6.914 -13.482 -21623 1.00 1.00OATOM 2380 CB HIS A1126 -7.080 -12.456 -18.280 1.00 1.00C
ATOM 2381 CG HIS A1126 -7.202 -11.063 -18.956 1.00 1.00CATOM 2382 ND1 HIS A1126 -6.166 -10.441 -19.455 1.00 1.00NATOM 2383 CD2 HIS A1126 -8.329 -10.294 -19.019 1.00 1.00CATOM 2384 CE1 HIS A1126 -6.548 -9.279 -19.848 1.00 1.00CATOM 2385 NE2 HIS A1126 -7.781 -9.120 -19.629 1.00 1.00NATOM 2386 HA HIS A1126 -7.018 -14.545 -18.918 1.00 1.00HATOM 2387 HB1 HIS A1126 -6.278 -12.316 -17.537 1.00 1.00HATOM 2388 HB2 HIS A1126 -8.052 -12.708 -17.805 1.00 1.00HATOM 2389 HD2 HIS A1126 -9.376 -10.455 -18.647 1.00 1.00HATOM 2390 HE1 HIS A1126 -5.979 -8.501 -20.367 1.00 1.00HATOM 2391 HD1 HIS A1126 -5.216 -10.784 -19.515 1.00 1.00HATOM 2392 HN HIS A1126 -5.036 -13.026 -20.428 1.00 1.00HATOM 2393 NGLY A1127 -8.898 -13.496 -20.516 1.00 1.00NATOM 2394 CA GLY A1127 -9.668 -13.355 -21.767 1.00 1.00CATOM 2395 CGLY A1127 -10.237 -11.998 -21.944 1.00 1.00CATOM 2396 OGLY A1127 -11.465 -11.858 -21.993 1.00 1.00OATOM 2397 HA2 GLY A1127 -10.460 -14.094 -21.701 1.00 1.00HATOM 2398 HA1 GLY A1127 -9.020 -13.607 -22.640 1.00 1.00HATOM 2399 HN GLY A1127 -9.347 -13.632 -19.630 1.00 1.00HATOM 2400 NTHR A1128 -9.443 -10.895 -22.071 1.00 1.00NATOM 2401 CA THR A1128 -9.879 -9.477 -22.130 1.00 1.00CATOM 2402 CTHR A1128 -10.967 -8.972 -21.152 1.00 1.00CATOM 2403 OTHR A1128 -10.816 -7.951 -20.500 1.00 1.00OATOM 2404 CB THR A1128 -10.195 -8.961 -23.559 1.00 1.00CATOM 2405 OG1 THR A1128 -10.607 -7.557 -23.529 1.00 1.00OATOM 2406 CG2 THR A1128 -11.136 -9.840 -24.374 1.00 1.00CATOM 2407 HA THR A1128 -9.023 -8.846 -21.812 1.00 1.00HATOM 2408 HB THR A1128 -9.248 -9.002 -24.138 1.00 1.00HATOM 2409 HG1 THR A1128 -11.496 -7.480 -23.184 1.00 1.00HATOM 2410 HG23 THR A1128 -11.298 -9.363 -25.332 1.00 1.00HATOM 2411 HG21 THR A1128 -12.111 -9.822 -23.850 1.00 1.00HATOM 2412 HG22 THR A1128 -10.734 -10.841 -24.417 1.00 1.00HATOM 2413 HN THR A1128 -8.454 -11.063 -22.019 1.00 1.00HATOM 2414 NMET A1129 -12.191 -9.636 -21.119 1.00 1.00NATOM 2415 CA MET A1129 -13.340 -9.053 -20.366 1.00 1.00CATOM 2416 CMET A1129 -13.954 -7.964 -21.239 1.00 1.00CATOM 2417 OMET A1129 -15.008 -8.202 -21.817 1.00 1.00OATOM 2418 CB MET A1129 -14.447 -10.107 -20.004 1.00 1.00CATOM 2419 CG MET A1129 -13.827 -11.324 -19.258 1.00 1.00CATOM 2420 SD MET A1129 -15.064 -12.387 -18.482 1.00 1.00SATOM 2421 CE MET A1129 -15.552 -13.170 -20.078 1.00 1.00CATOM 2422 HA MET A1129 -12.983 -8.545 -19.465 1.00 1.00HATOM 2423 HB1 MET A1129 -14.990 -10.467 -20.914 1.00 1.00HATOM 2424 HB2 MET A1129 -15.158 -9.608 -19.327 1.00 1.00HATOM 2425 HG1 MET A1129 -13.263 -10.919 -18.451 1.00 1.00HATOM 2426 HG2 MET A1129 -13.149 -11.860 -19.909 1.00 1.00HATOM 2427 HE1 MET A1129 -16.049 -12.422 -20.629 1.00 1.00HATOM 2428 HE2 MET A1129 -16.314 -13.940 -19.906 1.00 1.00HATOM 2429 HE3 MET A1129 -14.690 -13.602 -20.612 1.00 1.00HATOM 2430 HN MET A1129 -12.379 -10.471 -21.628 1.00 1.00HATOM 2431 NGLN A1130 -13.316 -6.777 -21.352 1.00 1.00NATOM 2432 CA GLN A1130 -13.896 -5.700 -22.115 1.00 1.00C
ATOM 2433 CGLN A1130 -12.820 -4.694 -22.434 1.00 1.00 CATOM 2434 OGLN A1130 -11.947 -4.537 -21.601 1.00 1.00 OATOM 2435 CB GLN A1130 -15.108 -5.124 -21.354 1.00 1.00 CATOM 2436 CG GLN A1130 -15.947 -4.150 -22.251 1.00 1.00 CATOM 2437 CD GLN A1130 -16.265 -4.686 -23.651 1.00 1.00 CATOM 2438 OE1 GLN A1130 -16.203 -3.930 -24.590 1.00 1.00 OATOM 2439 NE2 GLN A1130 -16.587 -5.989 -23.917 1.00 1.00 NATOM 2440 HA GLN A1130 -14.171 -6.163 -23.079 1.00 1.00 HATOM 2441 HB1 GLN A1130 -14.743 -4.629 -20.387 1.00 1.00 HATOM 2442 HB2 GLN A1130 -15.755 -5.951 -21.029 1.00 1.00 HATOM 2443 HG1 GLN A1130 -15.399 -3.220 -22.409 1.00 1.00 HATOM 2444 HG2 GLN A1130 -16.856 -3.773 -21.761 1.00 1.00 HATOM 2445 HE22 GLN A1130 -16.714 -6.359 -24.849 1.00 1.00 HATOM 2446 HE21 GLN A1130 -16.659 -6.665 -23.144 1.00 1.00 HATOM 2447 HN GLN A1130 -12.436 -6.641 -20.891 1.00 1.00 HATOM 2448 NASN A1131 -12.861 -4.077 -23.637 1.00 1.00 NATOM 2449 CA ASN A1131 -11.774 -3.125 -24.022 1.00 1.00 CATOM 2450 CASN A1131 -11.143 -2.310 -22.889 1.00 1.00 CATOM 2451 OASN A1131 -9.935 -2.368 -22.730 1.00 1.00 OATOM 2452 CB ASN A1131 -10.723 -3.897 -24.819 1.00 1.00 CATOM 2453 CG ASN A1131 -11.461 -4.622 -25.897 1.00 1.00 CATOM 2454 OD1 ASN A1131 -12.002 -3.971 -26.758 1.00 1.00 OATOM 2455 ND2 ASN A1131 -11.536 -5.968 -25.938 1.00 1.00 NATOM 2456 HA ASN A1131 -12.229 -2.370 -24.621 1.00 1.00 HATOM 2457 HB1 ASN A1131 -10.216 -4.616 -24.196 1.00 1.00 HATOM 2458 HB2 ASN A1131 -9.908 -3.327 -25.272 1.00 1.00 HATOM 2459 HD22 ASN A1131 -11.966 -6.412 -26.693 1.00 1.00 HATOM 2460 HD21 ASN A1131 -11.144 -6.582 -25.221 1.00 1.00 HATOM 2461 HN ASN A1131 -13.585 -4.260 -24.345 1.00 1.00 HATOM 2462 NLEU A1132 -12.023 -1.631 -22.086 1.00 1.00 NATOM 2463 CA LEU A1132 -11.514 -1.000 -20.872 1.00 1.00 CATOM 2464 CLEU A1132 -10.592 -1.923 -20.097 1.00 1.00 CATOM 2465 OLEU A1132 -9.443 -1.581 -19.943 1.00 1.00 OATOM 2466 CB LEU A1132 -12.627 -0.375 -19.965 1.00 1.00 CATOM 2467 CG LEU A1132 -12.323 0.858 -19.081 1.00 1.00 CATOM 2468 CD1 LEU A1132 -13.620 1.318 -18.335 1.00 1.00 CATOM 2469 CD2 LEU A1132 -11.117 0.659 -18.126 1.00 1.00 CATOM 2470 HA LEU A1132 -10.976 -0.094 -21.212 1.00 1.00 HATOM 2471 HB1 LEU A1132 -13.055 -1.152 -19.346 1.00 1.00 HATOM 2472 HB2 LEU A1132 -13.467 -0.043 -20.649 1.00 1.00 HATOM 2473 HG LEU A1132 -12.020 1.694 -19.677 1.00 1.00 HATOM 2474 HD21 LEU A1132 -11.341 -0.320 -17.621 1.00 1.00 HATOM 2475 HD22 LEU A1132 -10.920 1.421 -17.367 1.00 1.00 HATOM 2476 HD23 LEU A1132 -10.192 0.476 -18.718 1.00 1.00 HATOM 2477 HD11 LEU A1132 -14.093 0.452 -17.796 1.00 1.00 HATOM 2478 HD12 LEU A1132 -14.380 1.708 -19.043 1.00 1.00 HATOM 2479 HD13 LEU A1132 -13.357 2.113 -17.578 1.00 1.00 HATOM 2480 HN LEU A1132 -13.023 -1.690 -22.239 1.00 1.00 HATOM 2481 NHIS A1133 -11.044 -3.094 -19.593 1.00 1.00 NATOM 2482 CA HIS A1133 -10.145 -3.881 -18.744 1.00 1.00 CATOM 2483 CHIS A1133 -8.786 -4.227 -19.329 1.00 1.00 CATOM 2484 OHIS A1133 -7.773 -4.078 -18.649 1.00 1.00 O
ATOM 2485 CB HIS A1133 -10.796 -5.206 -18.318 1.00 1.00 CATOM 2486 CG HIS A1133 -9.812 -6.050 -17.522 1.00 1.00 CATOM 2487 ND1 HIS A1133 -8.852 -6.788 -18.045 1.00 1.00 NATOM 2488 CD2 HIS A1133 -9.788 -6.128 -16.183 1.00 1.00 CATOM 2489 CE1 HIS A1133 -8.154 -7.331 -17.095 1.00 1.00 CATOM 2490 NE2 HIS A1133 -8.660 -6.955 -15.993 1.00 1.00 NATOM 2491 HA HIS A1133 -9.963 -3.300 -17.867 1.00 1.00 HATOM 2492 HB1 HIS A1133 -11.092 -5.762 -19.250 1.00 1.00 HATOM 2493 HB2 HIS A1133 -11.701 -5.122 -17.695 1.00 1.00 HATOM 2494 HD2 HIS A1133 -10.411 -5.689 -15.393 1.00 1.00 HATOM 2495 HE1 HIS A1133 -7.299 -7.968 -17.206 1.00 1.00 HATOM 2496 HD1 HIS A1133 -8.744 -6.984 -19.051 1.00 1.00 HATOM 2497 HN HIS A1133 -12.003 -3.457 -19.702 1.00 1.00 HATOM 2498 NASP A1134 -8.750 -4.639 -20.615 1.00 1.00 NATOM 2499 CA ASP A1134 -7.421 -4.946 -21.196 1.00 1.00 CATOM 2500 CASP A1134 -6.575 -3.656 -21.330 1.00 1.00 CATOM 2501 OASP A1134 -5.377 -3.677 -21.118 1.00 1.00 OATOM 2502 CB ASP A1134 -7.599 -5.627 -22.575 1.00 1.00 CATOM 2503 CG ASP A1134 -6.322 -6.099 -23.228 1.00 1.00 CATOM 2504 OD1 ASP A1134 -5.650 -7.009 -22.629 1.00 1.00 OATOM 2505 OD2 ASP A1134 -5.934 -5.617 -24.324 1.00 1.00 OATOM 2506 HA ASP A1134 -6.910 -5.665 -20.546 1.00 1.00 HATOM 2507 H1B1 ASP A1134 -8.037 -4.845 -23.237 1.00 1.00 HATOM 2508 HB2 ASP A1134 -8.251 -6.507 -22.430 1.00 1.00 HATOM 2509 HN ASP A1134 -9.624 -4.719 -21.187 1.00 1.00 HATOM 2510 NSER A1135 -7.168 -2.496 -21.662 1.00 1.00 NATOM 2511 CA SER A1135 -6.404 -1.246 -21.574 1.00 1.00 CATOM 2512 CSER A1135 -5.891 -1.091 -20.164 1.00 1.00 CATOM 2513 OSER A1135 -4.752 -0.673 -20.085 1.00 1.00 OATOM 2514 CB SER A1135 -7.279 -0.039 -22.006 1.00 1.00 CATOM 2515 OG SER A1135 -7.944 0.549 -20.907 1.00 1.00 OATOM 2516 HA SER A1135 -5.542 -1.329 -22.221 1.00 1.00 HATOM 2517 HB1 SER A1135 -7.889 -0.137 -22.924 1.00 1.00 HATOM 2518 HB2 SER A1135 -6.571 0.742 -22.346 1.00 1.00 HATOM 2519 HG SER A1135 -8.574 -0.043 -20.516 1.00 1.00 HATOM 2520 HN SER A1135 -8.142 -2.430 -21.890 1.00 1.00 HATOM 2521 NCYS A1136 -6.703 -1.384 -19.118 1.00 1.00 NATOM 2522 CA CYS A1136 -6.169 -1.260 -17.793 1.00 1.00 CATOM 2523 CCYS A1136 -5.008 -2.168 -17.671 1.00 1.00 CATOM 2524 OCYS A1136 -3.912 -1.759 -17.253 1.00 1.00 OATOM 2525 CB CYS A1136 -7.148 -1.561 -16.614 1.00 1.00 CATOM 2526 SG CYS A1136 -8.668 -0.524 -16.550 1.00 1.00 SATOM 2527 HA CYS A1136 -5.856 -0.226 -17.702 1.00 1.00 HATOM 2528 HB1 CYS A1136 -7.444 -2.627 -16.544 1.00 1.00 HATOM 2529 HB2 CYS A1136 -6.658 -1.359 -15.625 1.00 1.00 HATOM 2530 HG CYS A1136 -8.854 -0.518 -15.536 1.00 1.00 HATOM 2531 HN CYS A1136 -7.613 -1.714 -19.285 1.00 1.00 HATOM 2532 NSER A1137 -5.153 -3.427 -18.041 1.00 1.00 NATOM 2533 CA SER A1137 -3.988 -4.337 -18.028 1.00 1.00 CATOM 2534 CSER A1137 -2.743 -3.650 -18.636 1.00 1.00 CATOM 2535 OSER A1137 -1.763 -3.564 -17.943 1.00 1.00 OATOM 2536 CB SER A1137 -4.329 -5.748 -18.488 1.00 1.00 C
ATOM 2537 OG SER A1137 -3.130 -6.487 -18.749 1.00 1.00 OATOM 2538 HA SER A1137 -3.687 -4.375 -16.989 1.00 1.00 HATOM 2539 HB1 SER A1137 -4.909 -5.517 -19.422 1.00 1.00 HATOM 2540 HB2 SER A1137 -5.039 -6.248 -17.822 1.00 1.00 HATOM 2541 HG SER A1137 -2.760 -6.824 -17.966 1.00 1.00 HATOM 2542 HN SER A1137 -6.113 -3.723 -18.329 1.00 1.00 HATOM 2543 NARG A1138 -2.760 -3.135 -19.883 1.00 1.00 NATOM 2544 CA ARG A1138 -1.490 -2.506 -20.364 1.00 1.00 CATOM 2545 CARG A1138 -1.156 -1.347 -19.425 1.00 1.00 CATOM 2546 OARG A1138 -0.035 -1.273 -18.948 1.00 1.00 OATOM 2547 CB ARG A1138 -1.474 -1.985 -21.854 1.00 1.00 CATOM 2548 CG ARG A1138 -0.850 -2.958 -22.900 1.00 1.00 CATOM 2549 CD ARG A1138 -1.951 -4.003 -23.330 1.00 1.00 CATOM 2550 NE ARG A1138 -2.270 -5.014 -22.332 1.00 1.00 NATOM 2551 CZ ARG A1138 -3.078 -6.021 -22.571 1.00 1.00 CATOM 2552 NH1 ARG A1138 -3.594 -6.290 -23.761 1.00 1.00 NATOM 2553 NH2 ARG A1138 -3.413 -6.877 -21.631 1.00 1.00 NATOM 2554 HA ARG A1138 -0.662 -3.208 -20.295 1.00 1.00 HATOM 2555 HB1 ARG A1138 -0.851 -1.067 -21.890 1.00 1.00 HATOM 2556 HB2 ARG A1138 -2.433 -1.533 -22.129 1.00 1.00 HATOM 2557 HG1 ARG A1138 0.097 -3.431 -22.566 1.00 1.00 HATOM 2558 HG2 ARG A1138 -0.597 -2.335 -23.760 1.00 1.00 HATOM 2559 HD1 ARG A1138 -1.663 -4.571 -24.152 1.00 1.00 HATOM 2560 HD2 ARG A1138 -2.886 -3.446 -23.541 1.00 1.00 HATOM 2561 HE ARG A1138 -1.822 -5.016 -21.444 1.00 1.00 HATOM 2562 HH12 ARG A1138 -4.216 -7.071 -23.937 1.00 1.00 HATOM 2563 HH11 ARG A1138 -3.449 -5.624 -24.533 1.00 1.00 HATOM 2564 HH22 ARG A1138 -4.175 -7.548 -21.819 1.00 1.00 HATOM 2565 HH21 ARG A1138 -2.961 -6.846 -20.686 1.00 1.00 HATOM 2566 HN ARG A1138 -3.593 -3.108 -20.451 1.00 1.00 HATOM 2567 NASN A1139 -2.124 -0.442 -19.278 1.00 1.00 NATOM 2568 CA ASN A1139 -1.752 0.806 -18.613 1.00 1.00 CATOM 2569 CASN A1139 -1.276 0.533 -17.233 1.00 1.00 CATOM 2570 OASN A1139 -0.390 1.278 -16.803 1.00 1.00 OATOM 2571 CB ASN A1139 -2.940 1.775 -18.582 1.00 1.00 CATOM 2572 CG ASN A1139 -2.470 3.027 -17.912 1.00 1.00 CATOM 2573 OD1 ASN A1139 -1.704 3.783 -18.533 1.00 1.00 OATOM 2574 ND2 ASN A1139 -2.887 3.279 -16.637 1.00 1.00 NATOM 2575 HA ASN A1139 -0.924 1.282 -19.175 1.00 1.00 HATOM 2576 HB1 ASN A1139 -3.830 1.377 -18.085 1.00 1.00 HATOM 2577 HB2 ASN A1139 -3.232 1.964 -19.623 1.00 1.00 HATOM 2578 HD22 ASN A1139 -2.557 4.103 -16.179 1.00 1.00 HATOM 2579 HD21 ASN A1139 -3.442 2.708 -16.055 1.00 1.00 HATOM 2580 HN ASN A1139 -3.046 -0.681 -19.541 1.00 1.00 HATOM 2581 NLEU A1140 -1.825 -0.469 -16.511 1.00 1.00 NATOM 2582 CA LEU A1140 -1.503 -0.630 -15.134 1.00 1.00 CATOM 2583 CLEU A1140 -0.074 -1.001 -15.080 1.00 1.00 CATOM 2584 OLEU A1140 0.668 -0.256 -14.438 1.00 1.00 OATOM 2585 CB LEU A1140 -2.462 -1.726 -14.560 1.00 1.00 CATOM 2586 CG LEU A1140 -2.349 -1.891 -12.978 1.00 1.00 CATOM 2587 CD1 LEU A1140 -3.437 -2.862 -12.414 1.00 1.00 CATOM 2588 CD2 LEU A1140 -0.947 -2.342 -12.573 1.00 1.00 C
ATOM 2589 HA LEU A1140-1.676 0.283 -14.549 1.00 1.00HATOM 2590 HB1 LEU A1140-2.280 -2.719 -15.105 1.00 1.00HATOM 2591 HB2 LEU A1140-3.494 -1.358 -14.755 1.00 1.00HATOM 2592 HG LEU A1140-2.530 -0.880 -12.549 1.00 1.00HATOM 2593 HD21 LEU A1140-0.988 -2.519 -11.465 1.00 1.00HATOM 2594 HD22 LEU A1140-0.258 -1.577 -12.562 1.00 1.00HATOM 2595 HD23 LEU A1140-0.619 -3.217 -13.135 1.00 1.00HATOM 2596 HD11 LEU A1140-3.229 -3.916 -12.710 1.00 1.00HATOM 2597 HD12 LEU A1140-4.398 -2.528 -12.848 1.00 1.00HATOM 2598 HD13 LEU A1140-3.490 -2.815 -11.339 1.00 1.00HATOM 2599 HN LEU A1140-2.322 -1.190 -16.955 1.00 1.00HATOM 2600 NTYR A1141 0.383 -2.084 -15.689 1.00 1.00NATOM 2601 CA TYR A1141 1.784 -2.353 -15.613 1.00 1.00CATOM 2602 CTYR A1141 2.679 -1.397 -16.383 1.00 1.00CATOM 2603 OTYR A1141 3.718 -0.994 -15.902 1.00 1.00OATOM 2604 CB TYR A1141 2.156 -3.870 -15.820 1.00 1.00CATOM 2605 CG TYR A1141 1.799 -4.310 -17.206 1.00 1.00CATOM 2606 CD1 TYR A1141 0.658 -5.128 -17.411 1.00 1.00CATOM 2607 CD2 TYR A1141 2.555 -3.963 -18.324 1.00 1.00CATOM 2608 CE1 TYR A1141 0.424 -5.669 -18.677 1.00 1.00CATOM 2609 CE2 TYR A1141 2.283 -4.471 -19.595 1.00 1.00CATOM 2610 CZ TYR A1141 1.179 -5.303 -19.809 1.00 1.00CATOM 2611 OH TYR A1141 0.806 -5.678 -21.128 1.00 1.00OATOM 2612 HA TYR A1141 2.132 -2.211 -14.595 1.00 1.00HATOM 2613 HB2 TYR A1141 1.532 -4.530 -15.146 1.00 1.00HATOM 2614 HB1 TYR A1141 3.187 -4.133 -15.579 1.00 1.00HATOM 2615 HD2 TYR A1141 3.406 -3.278 -18.207 1.00 1.00HATOM 2616 HE2 TYR A1141 2.965 -4.271 -20.413 1.00 1.00HATOM 2617 HE1 TYR A1141-0.403 -6.375 -18.788 1.00 1.00HATOM 2618 HD1 TYR A1141-0.041 -5.288 -16.591 1.00 1.00HATOM 2619 HH TYR A1141 0.986 -6.622 -21.139 1.00 1.00HATOM 2620 HN TYR A1141-0.164 -2.669 -16.233 1.00 1.00HATOM 2621 NVAL A1142 2.284 -0.965 -17.573 1.00 1.00NATOM 2622 CA VAL A1142 3.132 0.003 -18.277 1.00 1.00CATOM 2623 CVAL A1142 3.272 1.322 -17.482 1.00 1.00CATOM 2624 OVAL A1142 4.414 1.753 -17.297 1.00 1.00OATOM 2625 CB VAL A1142 2.604 0.393 -19.704 1.00 1.00CATOM 2626 CG1 VAL A1142 3.428 1.535 -20.262 1.00 1.00CATOM 2627 CG2 VAL A1142 2.523 -0.771 -20.695 1.00 1.00CATOM 2628 HA VAL A1142 4.140 -0.442 -18.370 1.00 1.00HATOM 2629 HB VAL A1142 1.562 0.790 -19.559 1.00 1.00HATOM 2630 HG11 VAL A1142 4.498 1.335 -20.198 1.00 1.00HATOM 2631 HG12 VAL A1142 3.225 2.481 -19.773 1.00 1.00HATOM 2632 HG13 VAL A1142 3.118 1.704 -21.325 1.00 1.00HATOM 2633 HG21 VAL A1142 3.502 -0.993 -21.152 1.00 1.00HATOM 2634 HG22 VAL A1142 1.806 -0.510 -21.502 1.00 1.00HATOM 2635 HG23 VAL A1142 2.227 -1.734 -20.170 1.00 1.00HATOM 2636 HN VAL A1142 1.421 -1.248 -17.995 1.00 1.00HATOM 2637 NSER A1143 2.189 1.974 -17.006 1.00 1.00NATOM 2638 CA SER A1143 2.399 3.147 -16.103 1.00 1.00CATOM 2639 CSER A1143 3.138 2.754 -14.853 1.00 1.00CATOM 2640 OSER A1143 4.127 3.430 -14.600 1.00 1.00O
ATOM 2641 CB SER A1143 1.0223.809 -15.734 1.00 1.00 CATOM 2642 OG SER A1143 0.1622.970 -14.923 1.00 1.00 OATOM 2643 HA SER A1143 3.0283.886 -16.594 1.00 1.00 HATOM 2644 HB1 SER A1143 0.4704.114 -16.650 1.00 1.00 HATOM 2645 HB2 SER A1143 1.1354.652 -15.026 1.00 1.00 HATOM 2646 HG SER A1143 -0.2742.263 -15.371 1.00 1.00 HATOM 2647 HN SER A1143 1.3221.603 -17.291 1.00 1.00 HATOM 2648 NLEU A1144 2.7001.761 -14.113 1.00 1.00 NATOM 2649 CA LEU A1144 3.4491.426 -12.920 1.00 1.00 CATOM 2650 CLEU A1144 4.9261.275 -13.269 1.00 1.00 CATOM 2651 OLEU A1144 5.6981.915 -12.547 1.00 1.00 OATOM 2652 CB LEU A1144 2.9180.101 -12.260 1.00 1.00 CATOM 2653 CG LEU A1144 3.749 -0.319 -11.032 1.00 1.00 CATOM 2654 CD1 LEU A1144 3.8620.771 -9.974 1.00 1.00 CATOM 2655 CD2 LEU A1144 3.087 -1.598 -10.405 1.00 1.00 CATOM 2656 HA LEU A1144 3.2532.264 -12.202 1.00 1.00 HATOM 2657 HB1 LEU A1144 2.919 -0.739 -12.963 1.00 1.00 HATOM 2658 HB2 LEU A1144 1.8630.233 -11.967 1.00 1.00 HATOM 2659 HG LEU A1144 4.791 -0.474 -11.397 1.00 1.00 HATOM 2660 HD21 LEU A1144 2.063 -1.472 -9.994 1.00 1.00 HATOM 2661 HD22 LEU A1144 3.780 -1.890 -9.612 1.00 1.00 HATOM 2662 HD23 LEU A1144 3.016 -2.422 -11.174 1.00 1.00 HATOM 2663 HD11 LEU A1144 4.4320.414 -9.119 1.00 1.00 HATOM 2664 HD12 LEU A1144 2.8921.166 -9.734 1.00 1.00 HATOM 2665 HD13 LEU A1144 4.4681.609 -10.331 1.00 1.00 HATOM 2666 HN LEU A1144 1.8301.316 -14.291 1.00 1.00 HATOM 2667 NLEU A1145 5.3690.609 -14.367 1.00 1.00 NATOM 2668 CA LEU A1145 6.7980.419 -14.652 1.00 1.00 CATOM 2669 CLEU A1145 7.5041.774 -14.700 1.00 1.00 CATOM 2670 OLEU A1145 8.5032.007 -14.047 1.00 1.00 OATOM 2671 CB LEU A1145 6.962 -0.392 -15.994 1.00 1.00 CATOM 2672 CG LEU A1145 8.499 -0.559 -16.314 1.00 1.00 CATOM 2673 CD1 LEU A1145 9.206 -1.431 -15.196 1.00 1.00 CATOM 2674 CD2 LEU A1145 8.648 -1.290 -17.707 1.00 1.00 CATOM 2675 HA LEU A1145 7.210 -0.120 -13.827 1.00 1.00 HATOM 2676 HB1 LEU A1145 6.5110.200 -16.814 1.00 1.00 HATOM 2677 HB2 LEU A1145 6.423 -1.338 -15.793 1.00 1.00 HATOM 2678 HG LEU A1145 9.1280.379 -16.455 1.00 1.00 HATOM 2679 HD21 LEU A1145 9.725 -1.542 -17.850 1.00 1.00 HATOM 2680 HD22 LEU A1145 8.432 -0.590 -18.517 1.00 1.00 HATOM 2681 HD23 LEU A1145 8.079 -2.249 -17.837 1.00 1.00 HATOM 2682 HD11 LEU A1145 10.154 -1.845 -15.455 1.00 1.00 HATOM 2683 HD12 LEU A1145 8.562 -2.304 -15.116 1.00 1.00 HATOM 2684 HD13 LEU A1145 9.309 -1.009 -14.204 1.00 1.00 HATOM 2685 HN LEU A1145 4.6960.273 -15.011 1.00 1.00 HATOM 2686 NLEU A1146 6.9182.685 -15.464 1.00 1.00 NATOM 2687 CA LEU A1146 7.4424.036 -15.545 1.00 1.00 CATOM 2688 CLEU A1146 7.4954.730 -14.233 1.00 1.00 CATOM 2689 OLEU A1146 8.4435.460 -13.920 1.00 1.00 OATOM 2690 CB LEU A1146 6.6494.932 -16.550 1.00 1.00 CATOM 2691 CG LEU A1146 6.6624.517 -18.052 1.00 1.00 CATOM 2692 CD1 LEU A1146 5.6855.455 -18.843 1.00 1.00 C
ATOM 2693 CD2 LEU A1146 8.0914.619 -18.721 1.00 1.00 CATOM 2694 HA LEU A1146 8.4343.905 -15.894 1.00 1.00 HATOM 2695 HB1 LEU A1146 7.1225.948 -16.481 1.00 1.00 HATOM 2696 HB2 LEU A1146 5.5974.987 -16.189 1.00 1.00 HATOM 2697 HG LEU A1146 6.3783.480 -18.230 1.00 1.00 HATOM 2698 HD21 LEU A1146 8.0374.511 -19.805 1.00 1.00 HATOM 2699 HD22 LEU A1146 8.7733.757 -18.392 1.00 1.00 HATOM 2700 HD23 LEU A1146 8.5435.582 -18.532 1.00 1.00 HATOM 2701 HD11 LEU A1146 4.6435.534 -18.439 1.00 1.00 HATOM 2702 HD12 LEU A1146 5.5775.272 -19.932 1.00 1.00 HATOM 2703 HD13 LEU A1146 6.0936.510 -18.691 1.00 1.00 HATOM 2704 HN LEU A1146 6.0932.485 -15.953 1.00 1.00 HATOM 2705 NLEU A1147 6.4724.539 -13.418 1.00 1.00 NATOM 2706 CA LEU A1147 6.4265.262 -12.130 1.00 1.00 CATOM 2707 CLEU A1147 7.4964.727 -11.210 1.00 1.00 CATOM 2708 OLEU A1147 8.3125.455 -10.630 1.00 1.00 OATOM 2709 CB LEU A1147 5.0795.276 -11.412 1.00 1.00 CATOM 2710 CG LEU A1147 3.9055.942 -12.191 1.00 1.00 CATOM 2711 CD1 LEU A1147 2.5485.729 -11.449 1.00 1.00 CATOM 2712 CD2 LEU A1147 4.2287.452 -12.438 1.00 1.00 CATOM 2713 HA LEU A1147 6.7446.293 -12.341 1.00 1.00 HATOM 2714 HB1 LEU A1147 5.2345.778 -10.454 1.00 1.00 HATOM 2715 HB2 LEU A1147 4.7384.274 -11.155 1.00 1.00 HATOM 2716 HG LEU A1147 3.7165.481 -13.166 1.00 1.00 HATOM 2717 HD21 LEU A1147 5.1227.611 -13.082 1.00 1.00 HATOM 2718 HD22 LEU A1147 4.3577.997 -11.499 1.00 1.00 HATOM 2719 HD23 LEU A1147 3.4317.933 -12.956 1.00 1.00 HATOM 2720 HD11 LEU A1147 2.3174.705 -11.189 1.00 1.00 HATOM 2721 HD12 LEU A1147 1.6946.176 -12.045 1.00 1.00 HATOM 2722 HD13 LEU A1147 2.4886.344 -10.524 1.00 1.00 HATOM 2723 HN LEU A1147 5.7733.835 -13.611 1.00 1.00 HATOM 2724 NTYR A1148 7.6353.388 -11.003 1.00 1.00 NATOM 2725 CA TYR A1148 8.8112.908 -10.275 1.00 1.00 CATOM 2726 CTYR A1148 10.073 3.391 -10.974 1.00 1.00 CATOM 2727 OTYR A1148 10.958 3.922 -10.372 1.00 1.00 OATOM 2728 CB TYR A1148 8.9081.365 -10.235 1.00 1.00 CATOM 2729 CG TYR A1148 10.112 0.898 -9.422 1.00 1.00 CATOM 2730 CD1 TYR A1148 11.403 0.925 -9.966 1.00 1.00 CATOM 2731 CD2 TYR A1148 9.9590.446 -8.092 1.00 1.00 CATOM 2732 CE1 TYR A1148 12.535 0.612 -9.198 1.00 1.00 CATOM 2733 CE2 TYR A1148 11.075 0.090 -7.346 1.00 1.00 CATOM 2734 CZ TYR A1148 12.367 0.063 -7.914 1.00 1.00 CATOM 2735 OH TYR A1148 13.452 -0.458 -7.222 1.00 1.00 OATOM 2736 HA TYR A1148 8.7713.256 -9.232 1.00 1.00 HATOM 2737 HB2 TYR A1148 8.8860.836 -11.209 1.00 1.00 HATOM 2738 HB1 TYR A1148 7.9891.022 -9.710 1.00 1.00 HATOM 2739 HD2 TYR A1148 8.9710.366 -7.706 1.00 1.00 HATOM 2740 HE2 TYR A1148 10.967 -0.221 -6.282 1.00 1.00 HATOM 2741 HE1 TYR A1148 13.517 0.683 -9.556 1.00 1.00 HATOM 2742 HD1 TYR A1148 11.486 1.142 -11.005 1.00 1.00 HATOM 2743 HH TYR A1148 13.851 -1.056 -7.845 1.00 1.00 HATOM 2744 HN TYR A1148 7.0462.706 -11.417 1.00 1.00 H
ATOM 2745 NGLN A1149 10.219 3.224 -12.304 1.00 1.00 NATOM 2746 CA GLN A1149 11.443 3.687 -12.927 1.00 1.00 CATOM 2747 CGLN A1149 11.689 5.187 -12.632 1.00 1.00 CATOM 2748 OGLN A1149 12.853 5.538 -12.515 1.00 1.00 OATOM 2749 CB GLN A1149 11.256 3.587 -14.433 1.00 1.00 CATOM 2750 CG GLN A1149 12.600 3.911 -15.217 1.00 1.00 CATOM 2751 CD GLN A1149 12.503 3.860 -16.762 1.00 1.00 CATOM 2752 OE1 GLN A1149 13.057 2.975 -17.381 1.00 1.00 OATOM 2753 NE2 GLN A1149 11.849 4.793 -17.445 1.00 1.00 NATOM 2754 HA GLN A1149 12.323 3.126 -12.571 1.00 1.00 HATOM 2755 HB1 GLN A1149 10.522 4.339 -14.776 1.00 1.00 HATOM 2756 HB2 GLN A1149 10.988 2.572 -14.723 1.00 1.00 HATOM 2757 HG1 GLN A1149 13.459 3.304 -14.947 1.00 1.00 HATOM 2758 HG2 GLN A1149 12.926 4.936 -14.961 1.00 1.00 HATOM 2759 HE22 GLN A1149 11.874 4.753 -18.448 1.00 1.00 HATOM 2760 HE21 GLN A1149 11.329 5.515 -16.973 1.00 1.00 HATOM 2761 HN GLN A1149 9.4752.777 -12.848 1.00 1.00 HATOM 2762 NTHR A1150 10.591 6.021 -12.564 1.00 1.00 NATOM 2763 CA THR A1150 10.744 7.475 -12.380 1.00 1.00 CATOM 2764 CTHR A1150 11.060 7.796 -10.909 1.00 1.00 CATOM 2765 OTHR A1150 12.048 8.480 -10.651 1.00 1.00 OATOM 2766 CB THR A1150 9.5648.339 -12.824 1.00 1.00 CATOM 2767 OG1 THR A1150 9.4368.261 -14.284 1.00 1.00 OATOM 2768 CG2 THR A1150 9.8739.776 -12.396 1.00 1.00 CATOM 2769 HA THR A1150 11.636 7.836 -12.963 1.00 1.00 HATOM 2770 HB THR A1150 8.5638.084 -12.381 1.00 1.00 HATOM 2771 HG1 THR A1150 9.0737.425 -14.633 1.00 1.00 HATOM 2772 HG23 THR A1150 9.20710.489 -12.807 1.00 1.00 HATOM 2773 HG21 THR A1150 10.835 10.125 -12.854 1.00 1.00 HATOM 2774 HG22 THR A1150 9.9129.914 -11.331 1.00 1.00 HATOM 2775 HN THR A1150 9.6275.761 -12.622 1.00 1.00 HATOM 2776 NPHE A1151 10.294 7.233 -9.883 1.00 1.00 NATOM 2777 CA PHE A1151 10.556 7.501 -8.450 1.00 1.00 CATOM 2778 CPHE A1151 11.306 6.307 -7.827 1.00 1.00 CATOM 2779 OPHE A1151 12.359 6.487 -7.220 1.00 1.00 OATOM 2780 CB PHE A1151 9.2127.887 -7.671 1.00 1.00 CATOM 2781 CG PHE A1151 8.6318.999 -8.531 1.00 1.00 CATOM 2782 CD1 PHE A1151 9.28710.240 -8.573 1.00 1.00 CATOM 2783 CD2 PHE A1151 7.5308.747 -9.346 1.00 1.00 CATOM 2784 CE1 PHE A1151 8.83911.187 -9.500 1.00 1.00 CATOM 2785 CE2 PHE A1151 7.1699.679 -10.309 1.00 1.00 CATOM 2786 CZ PHE A1151 7.80110.902 -10.380 1.00 1.00 CATOM 2787 HA PHE A1151 11.298 8.301 -8.417 1.00 1.00 HATOM 2788 HB1 PHE A1151 9.3568.287 -6.641 1.00 1.00 HATOM 2789 HB2 PHE A1151 8.5357.032 -7.662 1.00 1.00 HATOM 2790 HD2 PHE A1151 6.9717.846 -9.252 1.00 1.00 HATOM 2791 HE2 PHE A1151 6.3359.380 -10.999 1.00 1.00 HATOM 2792 HZ PHE A1151 7.54911.606 -11.159 1.00 1.00 HATOM 2793 HE1 PHE A1151 9.35912.146 -9.558 1.00 1.00 HATOM 2794 HD1 PHE A1151 10.026 10.410 -7.850 1.00 1.00 HATOM 2795 HN PHE A1151 9.5346.684 -10.145 1.00 1.00 HATOM 2796 NGLY A1152 10.678 5.116 -7.944 1.00 1.00 N
ATOM 2797 CA GLY A1152 11.260 3.951 -7.322 1.00 1.00 CATOM 2798 CGLY A1152 11.359 3.942 -5.869 1.00 1.00 CATOM 2799 OGLY A1152 10.586 3.257 -5.193 1.00 1.00 OATOM 2800 HA2 GLY A1152 12.251 3.836 -7.787 1.00 1.00 HATOM 2801 HA1 GLY A1152 10.669 3.030 -7.635 1.00 1.00 HATOM 2802 HN GLY A1152 9.8245.093 -8.451 1.00 1.00 HATOM 2803 NARG A1153 12.328 4.704 -5.332 1.00 1.00 NATOM 2804 CA ARG A1153 12.698 4.574 -3.931 1.00 1.00 CATOM 2805 CARG A1153 12.956 5.904 -3.260 1.00 1.00 CATOM 2806 OARG A1153 13.006 6.858 -4.013 1.00 1.00 OATOM 2807 CB ARG A1153 13.924 3.600 -3.885 1.00 1.00 CATOM 2808 CG ARG A1153 13.435 2.139 -4.075 1.00 1.00 CATOM 2809 CD ARG A1153 14.566 1.045 -4.103 1.00 1.00 CATOM 2810 NE ARG A1153 13.920 -0.191 -4.490 1.00 1.00 NATOM 2811 CZ ARG A1153 13.389 -0.997 -3.593 1.00 1.00 CATOM 2812 NH1 ARG A1153 13.407 -0.844 -2.298 1.00 1.00 NATOM 2813 NH2 ARG A1153 12.720 -1.994 -4.101 1.00 1.00 NATOM 2814 HA ARG A1153 11.814 4.217 -3.359 1.00 1.00 HATOM 2815 HB1 ARG A1153 14.448 3.728 -2.939 1.00 1.00 HATOM 2816 HB2 ARG A1153 14.676 3.819 -4.699 1.00 1.00 HATOM 2817 HG1 ARG A1153 12.951 2.076 -5.021 1.00 1.00 HATOM 2818 HG2 ARG A1153 12.701 1.812 -3.267 1.00 1.00 HATOM 2819 HD1 ARG A1153 15.202 1.099 -3.260 1.00 1.00 HATOM 2820 HD2 ARG A1153 15.264 1.417 -4.894 1.00 1.00 HATOM 2821 HE ARG A1153 13.874 -0.374 -5.512 1.00 1.00 HATOM 2822 HH12 ARG A1153 12.833 -1.483 -1.758 1.00 1.00 HATOM 2823 HH11 ARG A1153 14.027 -0.175 -1.807 1.00 1.00 HATOM 2824 HH22 ARG A1153 12.271 -2.669 -3.458 1.00 1.00 HATOM 2825 HH21 ARG A1153 12.614 -2.141 -5.096 1.00 1.00 HATOM 2826 HN ARG A1153 12.963 5.221 -5.880 1.00 1.00 HATOM 2827 NLYS A1154 13.123 6.053 -1.922 1.00 1.00 NATOM 2828 CA LYS A1154 12.885 5.004 -0.957 1.00 1.00 CATOM 2829 CLYS A1154 11.483 5.298 -0.382 1.00 1.00 CATOM 2830 OLYS A1154 11.440 6.156 0.480 1.00 1.00 OATOM 2831 CB LYS A1154 14.028 5.115 0.083 1.00 1.00 CATOM 2832 CG LYS A1154 13.714 4.114 1.242 1.00 1.00 CATOM 2833 CD LYS A1154 14.699 4.185 2.419 1.00 1.00 CATOM 2834 CE LYS A1154 14.550 3.088 3.518 1.00 1.00 CATOM 2835 NZ LYS A1154 14.928 1.682 3.208 1.00 1.00 NATOM 2836 HA LYS A1154 12.847 3.988 -1.343 1.00 1.00 HATOM 2837 HB1 LYS A1154 14.060 6.127 0.459 1.00 1.00 HATOM 2838 HB2 LYS A1154 14.956 4.857 -0.417 1.00 1.00 HATOM 2839 HG1 LYS A1154 13.754 3.086 0.819 1.00 1.00 HATOM 2840 HG2 LYS A1154 12.772 4.250 1.740. 1.00 1.00 HATOM 2841 HD1 LYS A1154 14.559 5.190 2.845 1.00 1.00 HATOM 2842 HD2 LYS A1154 15.753 4.078 2.079 1.00 1.00 HATOM 2843 HE1 LYS A1154 13.478 3.095 3.743 1.00 1.00 HATOM 2844 HE2 LYS A1154 15.038 3.438 4.413 1.00 1.00 HATOM 2845 HZ1 LYS A1154 14.808 1.217 4.145 1.00 1.00 HATOM 2846 HZ2 LYS A1154 15.916 1.486 2.925 1.00 1.00 HATOM 2847 HZ3 LYS A1154 14.326 1.121 2.448 1.00 1.00 HATOM 2848 HN LYS A1154 13.261 6.982 -1.580 1.00 1.00 H
ATOM 2849 NLEU A1155 10.368 4.584 -0.750 1.00 1.00 NATOM 2850 CA LEU A1155 9.192 4.686 0.056 1.00 1.00 CATOM 2851 CLEU A1155 9.454 4.272 1.528 1.00 1.00 CATOM 2852 OLEU A1155 9.425 3.096 1.843 1.00 1.00 OATOM 2853 CB LEU A1155 8.070 3.732 -0.516 1.00 1.00 CATOM 2854 CG LEU A1155 6.733 3.804 0.233 1.00 1.00 CATOM 2855 CD1 LEU A1155 6.017 5.197 0.245 1.00 1.00 CATOM 2856 CD2 LEU A1155 5.779 2.774 -0.382 1.00 1.00 CATOM 2857 HA LEU A1155 8.899 5.768 0.040 1.00 1.00 HATOM 2858 HB1 LEU A1155 8.525 2.739 -0.516 1.00 1.00 HATOM 2859 HB2 LEU A1155 7.831 4.106 -1.548 1.00 1.00 HATOM 2860 HG LEU A1155 6.798 3.641 1.377 1.00 1.00 HATOM 2861 HD21 LEU A1155 6.137 1.752 -0.319 1.00 1.00 HATOM 2862 HD22 LEU A1155 5.518 3.025 -1.400 1.00 1.00 HATOM 2863 HD23 LEU A1155 4.827 2.798 0.218 1.00 1.00 HATOM 2864 HD11 LEU A1155 5.743 5.472 -0.762 1.00 1.00 HATOM 2865 HD12 LEU A1155 6.682 5.959 0.634 1.00 1.00 HATOM 2866 HD13 LEU A1155 5.069 5.216 0.849 1.00 1.00 HATOM 2867 HN LEU A1155 10.423 3.905 -1.482 1.00 1.00 HATOM 2868 NHIS A1156 9.737 5.208 2.450 1.00 1.00 NATOM 2869 CA HIS A1156 9.937 4.900 3.870 1.00 1.00 CATOM 2870 CHIS A1156 8.638 4.596 4.513 1.00 1.00 CATOM 2871 OHIS A1156 8.137 5.370 5.304 1.00 1.00 OATOM 2872 CB HIS A1156 10.778 6.053 4.518 1.00 1.00 CATOM 2873 CG HIS A1156 11.137 5.771 5.990 1.00 1.00 CATOM 2874 ND1 HIS A1156 10.280 5.762 7.009 1.00 1.00 NATOM 2875 CD2 HIS A1156 12.395 5.511 6.428 1.00 1.00 CATOM 2876 CE1 HIS A1156 10.983 5.441 8.080 1.00 1.00 CATOM 2877 NE2 HIS A1156 12.187 5.303 7.828 1.00 1.00 NATOM 2878 HA HIS A1156 10.555 3.969 3.846 1.00 1.00 HATOM 2879 HB1 HIS A1156 10.215 6.990 4.425 1.00 1.00 HATOM 2880 HB2 HIS A1156 11.651 6.133 3.910 1.00 1.00 HATOM 2881 HD2 HIS A1156 13.319 5.448 5.878 1.00 1.00 HATOM 2882 HE1 HIS A1156 10.519 5.296 9.076 1.00 1.00 HATOM 2883 HD1 HIS A1156 9.234 5.916 6.960 1.00 1.00 HATOM 2884 HN HIS A1156 9.803 6.186 2.155 1.00 1.00 HATOM 2885 NLEU A1157 8.056 3.445 4.117 1.00 1.00 NATOM 2886 CA LEU A1157 6.794 2.916 4.719 1.00 1.00 CATOM 2887 CLEU A1157 7.007 2.809 6.217 1.00 1.00 CATOM 2888 OLEU A1157 8.154 2.531 6.571 1.00 1.00 OATOM 2889 CB LEU A1157 6.297 1.635 3.970 1.00 1.00 CATOM 2890 CG LEU A1157 5.014 0.959 4.584 1.00 1.00 CATOM 2891 CD1 LEU A1157 4.339 0.197 3.476 1.00 1.00 CATOM 2892 CD2 LEU A1157 5.392 -0.021 5.734 1.00 1.00 CATOM 2893 HA LEU A1157 6.037 3.672 4.525 1.00 1.00 HATOM 2894 HB1 LEU A1157 7.114 0.885 4.019 1.00 1.00 HATOM 2895 HB2 LEU A1157 6.159 1.863 2.912 1.00 1.00 HATOM 2896 HG LEU A1157 4.421 1.723 5.056 1.00 1.00 HATOM 2897 HD21 LEU A1157 4.528 -0.445 6.240 1.00 1.00 HATOM 2898 HD22 LEU A1157 6.064 0.440 6.497 1.00 1.00 HATOM 2899 HD23 LEU A1157 6.005 -0.778 5.302 1.00 1.00 HATOM 2900 HD11 LEU A1157 5.089 -0.382 2.889 1.00 1.00 H
ATOM 2901 HD12 LEU A1157 3.688 -0.601 3.806 1.00 1.00HATOM 2902 HD13 LEU A1157 3.823 0.950 2.853 1.00 1.00HATOM 2903 HN LEU A1157 8.415 2.896 3.377 1.00 1.00HATOM 2904 NTYR A1158 6.001 2.997 7.112 1.00 1.00NATOM 2905 CA TYR A1158 6.353 2.691 8.492 1.00 1.00CATOM 2906 CTYR A1158 5.180 2.340 9.420 1.00 1.00CATOM 2907 OTYR A1158 5.231 2.582 10.620 1.00 1.00OATOM 2908 CB TYR A1158 7.108 3.911 9.064 1.00 1.00CATOM 2909 CG TYR A1158 6.248 5.186 9.219 1.00 1.00CATOM 2910 CD1 TYR A1158 5.856 5.665 10.473 1.00 1.00CATOM 2911 CD2 TYR A1158 5.938 5.989 8.107 1.00 1.00CATOM 2912 CE1 TYR A1158 5.305 6.954 10.640 1.00 1.00CATOM 2913 CE2 TYR A1158 5.365 7.274 8.256 1.00 1.00CATOM 2914 CZ TYR A1158 5.140 7.799 9.536 1.00 1.00CATOM 2915 OH TYR A1158 4.730 9.142 9.708 1.00 1.00OATOM 2916 HA TYR A1158 6.993 1.801 8.552 1.00 1.00HATOM 2917 HB2 TYR A1158 7.952 4.117 8.428 1.00 1.00HATOM 2918 HB1 TYR A1158 7.505 3.602 10.063 1.00 1.00HATOM 2919 HD2 TYR A1158 6.128 5.658 7.128 1.00 1.00HATOM 2920 HE2 TYR A1158 5.152 7.853 7.423 1.00 1.00HATOM 2921 HE1 TYR A1158 5.011 7.328 11.643 1.00 1.00HATOM 2922 HD1 TYR A1158 6.076 5.039 11.331 1.00 1.00HATOM 2923 HH TYR A1158 4.229 9.453 8.961 1.00 1.00HATOM 2924 HN TYR A1158 5.103 3.351 6.854 1.00 1.00HATOM 2925 NSER A1159 4.126 1.736 8.901 1.00 1.00NATOM 2926 CA SER A1159 3.050 1.306 9.867 1.00 1.00CATOM 2927 CSER A1159 3.532 0.234 10.847 1.00 1.00CATOM 2928 OSER A1159 3.112 0.276 12.022 1.00 1.00OATOM 2929 CB SER A1159 1.900 0.681 9.043 1.00 1.00CATOM 2930 OG SER A1159 0.955 0.054 9.927 1.00 1.00OATOM 2931 HA SER A1159 2.737 2.175 10.411 1.00 1.00HATOM 2932 HB1 SER A1159 2.270 -0.076 8.309 1.00 1.00HATOM 2933 HB2 SER A1159 1.416 1.452 8.527 1.00 1.00HATOM 2934 HG SER A1159 0.221 -0.389 9.507 1.00 1.00HATOM 2935 HN SER A1159 4.069 1.542 7.910 1.00 1.00HATOM 2936 CB HIE A1160 4.117 -3.099 10.768 1.00 1.00CATOM 2937 CG HIE A1160 4.124 -4.317 11.624 1.00 1.00CATOM 2938 ND1 HIE A1160 4.956 -4.587 12.771 1.00 1.00NATOM 2939 CD2 HIE A1160 3.396 -5.438 11.595 1.00 1.00CATOM 2940 CE1 HIE A1160 4.629 -5.686 13.310 1.00 1.00CATOM 2941 NHIE A1160 4.296 -0.779 10.385 1.00 1.00NATOM 2942 CA HIE A1160 4.764 -1.796 11.317 1.00 1.00CATOM 2943 CHIE A1160 6.255 -1.683 11.254 1.00 1.00CATOM 2944 OHIE A1160 6.830 -2.629 10.714 1.00 1.00OATOM 2945 HB2 HIE A1160 4.557 -3.371 9.774 1.00 1.00HATOM 2946 NE2 HIE A1160 3.708 -6.240 12.583 1.00 1.00NATOM 2947 HB1 HIE A1160 3.051 -2.840 10.493 1.00 1.00HATOM 2948 HA HIE A1160 4.444 -1.752 12.362 1.00 1.00HATOM 2949 HD2 HIE A1160 2.690 -5.691 10.834 1.00 1.00HATOM 2950 HE1 HIE A1160 5.062 -6.124 14.199 1.00 1.00HATOM 2951 HHIE A1160 4.535 -0.797 9.393 1.00 1.00HATOM 2952 HE2 HIE A1160 3.265 -7.102 12.803 1.00 1.00H
ATOM 2953 NPRO A1161 6.878 -0.617 11.721 1.00 1.00NATOM 2954 CA PRO A1161 8.205 -0.223 11.276 1.00 1.00CATOM 2955 CPRO A1161 9.034 -1.099 10.378 1.00 1.00CATOM 2956 OPRO A1161 10.041 -1.609 10.812 1.00 1.00OATOM 2957 CB PRO A1161 8.8150.267 12.641 1.00 1.00CATOM 2958 CG PRO A1161 7.5970.913 13.337 1.00 1.00CATOM 2959 CD PRO A1161 6.3270.101 12.818 1.00 1.00CATOM 2960 HA PRO A1161 8.1470.686 10.627 1.00 1.00HATOM 2961 HD2 PRO A1161 6.004 -0.539 13.658 1.00 1.00HATOM 2962 HD1 PRO A1161 5.5110.708 12.448 1.00 1.00HATOM 2963 HG2 PRO A1161 7.7061.032 14.432 1.00 1.00HATOM 2964 HG1 PRO A1161 7.4521.930 12.974 1.00 1.00HATOM 2965 HB1 PRO A1161 9.6461.022 12.625 1.00 1.00HATOM 2966 HB2 PRO A1161 9.075 -0.599 13.268 1.00 1.00HATOM 2967 NILE A1162 8.492 -1.232 9.1781.00 1.00NATOM 2968 CA ILE A1162 9.331 -1.794 8.1071.00 1.00CATOM 2969 CILE A1162 9.517 -0.643 7.0631.00 1.00CATOM 2970 OILE A1162 8.5500.090 6.7791.00 1.00OATOM 2971 CB ILE A1162 8.575 -3.048 7.5121.00 1.00CATOM 2972 CG1 ILE A1162 8.937 -4.316 8.3761.00 1.00CATOM 2973 CG2 ILE A1162 8.806 -3.205 6.0081.00 1.00CATOM 2974 CD1 ILE A1162 8.327 -5.606 7.7911.00 1.00CATOM 2975 HA ILE A1162 10.332 -2.034 8.4961.00 1.00HATOM 2976 HB ILE A1162 7.484 -2.938 7.6291.00 1.00HATOM 2977 HG11 ILE A1162 8.690 -4.246 9.4291.00 1.00HATOM 2978 HG12 ILE A1162 10.041 -4.429 8.2241.00 1.00HATOM 2979 HD11 ILE A1162 8.503 -6.402 8.4891.00 1.00HATOM 2980 HD12 ILE A1162 8.803 -5.952 6.8271.00 1.00HATOM 2981 HD13 ILE A1162 7.303 -5.531 7.5081.00 1.00HATOM 2982 HG21 ILE A1162 9.848 -3.338 5.85.3 1.00 1.00HATOM 2983 HG22 ILE A1162 8.544 -2.271 5.5301.00 1.00HATOM 2984 HG23 ILE A1162 8.243 -4.016 5.4701.00 1.00HATOM 2985 HN ILE A1162 7.605 -0.891 8.8771.00 1.00HATOM 2986 NILE A1163 10.738 -0.465 6.5471.00 1.00NATOM 2987 CA ILE A1163 11.014 0.720 5.6971.00 1.00CATOM 2988 CILE A1163 11.721 0.253 4.4501.00 1.00CATOM 2989 OILE A1163 12.775 0.651 4.0611.00 1.00OATOM 2990 CB ILE A1163 11.904 1.702 6.5501.00 1.00CATOM 2991 CG1 ILE A1163 13.188 0.985 7.0601.00 1.00CATOM 2992 CG2 ILE A1163 11.073 2.232 7.7201.00 1.00CATOM 2993 CD1 ILE A1163 14.275 1.954 7.6171.00 1.00CATOM 2994 HA ILE A1163 10.135 1.241 5.3251.00 1.00HATOM 2995 HB ILE A1163 12.159 2.543 5.8851.00 1.00HATOM 2996 HG11 ILE A1163 13.701 0.327 6.3571.00 1.00HATOM 2997 HG12 ILE A1163 12.875 0.311 7.8581.00 1.00HATOM 2998 HD11 ILE A1163 14.652 2.557 6.8011.00 1.00HATOM 2999 HD12 ILE A1163 15.123 1.296 7.9561.00 1.00HATOM 3000 HD13 ILE A1163 14.021 2.542 8.4941.00 1.00HATOM 3001 HG21 ILE A1163 10.265 2.852 7.3511.00 1.00HATOM 3002 HG22 ILE A1163 11.752 2.895 8.3241.00 1.00HATOM 3003 HG23 ILE A1163 10.673 1.425 8.3351.00 1.00HATOM 3004 HN ILE A1163 11.524 -1.071 6.7241.00 1.00H
ATOM 3005 NLEU A1164 11.055 -0.722 3.715 1.00 1.00 NATOM 3006 CA LEU A1164 11.716 -1.337 2.536 1.00 1.00 CATOM 3007 CLEU A1164 12.153 -0.249 1.560 1.00 1.00 CATOM 3008 OLEU A1164 13.360 -0.138 1.377 1.00 1.00 OATOM 3009 CB LEU A1164 10.820 -2.370 1.756 1.00 1.00 CATOM 3010 CG LEU A1164 10.336 -3.635 2.607 1.00 1.00 CATOM 3011 CD1 LEU A1164 9.303 -4.595 1.989 1.00 1.00 CATOM 3012 CD2 LEU A1164 11.516 -4.513 3.067 1.00 1.00 CATOM 3013 HA LEU A1164 12.599 -1.940 2.915 1.00 1.00 HATOM 3014 HB1 LEU A1164 9.884 -1.968 1.350 1.00 1.00 HATOM 3015 HB2 LEU A1164 11.389 -2.781 0.892 1.00 1.00 HATOM 3016 HG LEU A1164 9.869 -3.292 3.491 1.00 1.00 HATOM 3017 HD21 LEU A1164 11.231 -5.492 3.488 1.00 1.00 HATOM 3018 HD22 LEU A1164 12.107 -3.960 3.875 1.00 1.00 HATOM 3019 HD23 LEU A1164 12.142 -4.758 2.183 1.00 1.00 HATOM 3020 HD11 LEU A1164 8.983 -5.300 2.793 1.00 1.00 HATOM 3021 HD12 LEU A1164 9.796 -5.124 1.130 1.00 1.00 HATOM 3022 HD13 LEU A1164 8.478 -4.091 1.523 1.00 1.00 HATOM 3023 HN LEU A1164 10.234 -1.147 4.022 1.00 1.00 HATOM 3024 NGLY A1165 11.219 0.537 0.997 1.00 1.00 NATOM 3025 CA GLY A1165 11.501 1.442 -0.081 1.00 1.00 CATOM 3026 CGLY A1165 10.576 1.497 -1.276 1.00 1.00 CATOM 3027 OGLY A1165 10.674 2.392 -2.095 1.00 1.00 OATOM 3028 HA2 GLY A1165 12.540 1.298 -0.504 1.00 1.00 HATOM 3029 HA1 GLY A1165 11.423 2.417 0.327 1.00 1.00 HATOM 3030 HN GLY A1165 10.257 0.482 1.374 1.00 1.00 HATOM 3031 NPHE A1166 9.651 0.513 -1.452 1.00 1.00 NATOM 3032 CA PHE A1166 8.673 0.625 -2.474 1.00 1.00 CATOM 3033 CPHE A1166 7.432 -0.191 -2.246 1.00 1.00 CATOM 3034 OPHE A1166 7.608 -1.168 -1.595 1.00 1.00 OATOM 3035 CB PHE A1166 9.362 0.029 -3.755 1.00 1.00 CATOM 3036 CG PHE A1166 8.326 -0.256 -4.883 1.00 1.00 CATOM 3037 CD1 PHE A1166 7.643 0.785 -5.571 1.00 1.00 CATOM 3038 CD2 PHE A1166 8.019 -1.608 -5.280 1.00 1.00 CATOM 3039 CE1 PHE A1166 6.659 0.502 -6.520 1.00 1.00 CATOM 3040 CE2 PHE A1166 7.002 -1.864 -6.217 1.00 1.00 CATOM 3041 CZ PHE A1166 6.355 -0.820 -6.867 1.00 1.00 CATOM 3042 HA PHE A1166 8.309 1.654 -2.556 1.00 1.00 HATOM 3043 HB1 PHE A1166 10.057 -0.772 -3.542 1.00 1.00 HATOM 3044 HB2 PHE A1166 10.062 0.875 -4.068 1.00 1.00 HATOM 3045 HD2 PHE A1166 8.638 -2.405 -4.844 1.00 1.00 HATOM 3046 HE2 PHE A1166 6.722 -2.847 -6.493 1.00 1.00 HATOM 3047 HZ PHE A1166 5.680 -1.027 -7.621 1.00 1.00 HATOM 3048 HE1 PHE A1166 6.110 1.250 -7.070 1.00 1.00 HATOM 3049 HD1 PHE A1166 7.814 1.866 -5.413 1.00 1.00 HATOM 3050 HN PHE A1166 9.555 -0.261 -0.850 1.00 1.00 HATOM 3051 NARG A1167 6.223 0.175 -2.711 1.00 1.00 NATOM 3052 CA ARG A1167 5.018 -0.721 -2.779 1.00 1.00 CATOM 3053 CARG A1167 3.816 0.159 -3.052 1.00 1.00 CATOM 3054 OARG A1167 3.293 0.126 -4.180 1.00 1.00 OATOM 3055 CB ARG A1167 4.763 -1.609 -1.520 1.00 1.00 CATOM 3056 CG ARG A1167 5.473 -2.994 -1.711 1.00 1.00 C
ATOM 3057 CD ARG A1167 5.895 -3.551 -0.303 1.00 1.00 CATOM 3058 NE ARG A1167 6.782 -4.733 -0.583 1.00 1.00 NATOM 3059 CZ ARG A1167 8.042 -4.620 -0.945 1.00 1.00 CATOM 3060 NH1 ARG A1167 8.670 -3.510 -1.162 1.00 1.00 NATOM 3061 NH2 ARG A1167 8.739 -5.734 -1.067 1.00 1.00 NATOM 3062 HA ARG A1167 5.074 -1.365 -3.664 1.00 1.00 HATOM 3063 HB1 ARG A1167 3.684 -1.817 -1.326 1.00 1.00 HATOM 3064 HB2 ARG A1167 5.131 -1.109 -0.576 1.00 1.00 HATOM 3065 HG1 ARG A1167 6.348 -2.908 -2.430 1.00 1.00 HATOM 3066 HG2 ARG A1167 4.693 -3.640 -2.192 1.00 1.00 HATOM 3067 HD1 ARG A1167 6.419 -2.927 0.425 1.00 1.00 HATOM 3068 HD2 ARG A1167 4.939 -3.815 0.183 1.00 1.00 HATOM 3069 HE ARG A1167 6.383 -5.638 -0.393 1.00 1.00 HATOM 3070 HH12 ARG A1167 9.691 -3.482 -1.363 1.00 1.00 HATOM 3071 HH11 ARG A1167 8.209 -2.618 -1.075 1.00 1.00 HATOM 3072 HH22 ARG A1167 9.726 -5.676 -1.363 1.00 1.00 HATOM 3073 HH21 ARG A1167 8.321 -6.639 -0.932 1.00 1.00 HATOM 3074 HN ARG A1167 6.131 1.018 -3.197 1.00 1.00 HATOM 3075 NLYS A1168 3.281 0.928 -2.076 1.00 1.00 NATOM 3076 CA LYS A1168 2.253 1.911 -2.360 1.00 1.00 CATOM 3077 CLYS A1168 3.037 3.035 -3.011 1.00 1.00 CATOM 3078 OLYS A1168 3.463 3.913 -2.284 1.00 1.00 OATOM 3079 CB LYS A1168 1.475 2.285 -1.102 1.00 1.00 CATOM 3080 CG LYS A1168 0.106 2.991 -1.428 1.00 1.00 CATOM 3081 CD LYS A1168 0.031 4.160 -2.384 1.00 1.00 CATOM 3082 CE LYS A1168 -1.465 4.592 -2.743 1.00 1.00 CATOM 3083 NZ LYS A1168 -2.334 3.454 -3.242 1.00 1.00 NATOM 3084 HA LYS A1168 1.553 1.556 -3.100 1.00 1.00 HATOM 3085 HB1 LYS A1168 2.081 2.987 -0.512 1.00 1.00 HATOM 3086 HB2 LYS A1168 1.369 1.404 -0.457 1.00 1.00 HATOM 3087 HG1 LYS A1168 -0.548 2.255 -1.820 1.00 1.00 HATOM 3088 HG2 LYS A1168 -0.295 3.299 -0.451 1.00 1.00 HATOM 3089 HD1 LYS A1168 0.501 5.018 -1.893 1.00 1.00 HATOM 3090 HD2 LYS A1168 0.491 3.950 -3.365 1.00 1.00 HATOM 3091 HE1 LYS A1168 -1.457 5.419 -3.494 1.00 1.00 HATOM 3092 HE2 LYS A1168 -1.865 5.025 -1.793 1.00 1.00 HATOM 3093 HZ1 LYS A1168 -1.872 2.865 -4.054 1.00 1.00 HATOM 3094 HZ2 LYS A1168 -2.746 2.731 -2.542 1.00 1.00 HATOM 3095 HZ3 LYS A1168 -3.346 3.762 -3.546 1.00 1.00 HATOM 3096 HN LYS A1168 3.622 0.917 -1.121 1.00 1.00 HATOM 3097 NILE A1169 3.300 2.959 -4.356 1.00 1.00 NATOM 3098 CA ILE A1169 4.018 4.049 -5.018 1.00 1.00 CATOM 3099 CILE A1169 3.540 5.362 4.450 1.00 1.00 CATOM 3100 OILE A1169 2.314 5.567 -4.363 1.00 1.00 OATOM 3101 CB ILE A1169 3.841 3.961 -6.579 1.00 1.00 CATOM 3102 CG1 ILE A1169 4.675 4.971 -7.397 1.00 1.00 CATOM 3103 CG2 ILE A1169 2.377 4.226 -6.992 1.00 1.00 CATOM 3104 CD1 ILE A1169 6.056 4.377 -7.688 1.00 1.00 CATOM 3105 HA ILE A1169 5.048 3.915 4.745 1.00 1.00 HATOM 3106 HB ILE A1169 4.130 2.926 -6.782 1.00 1.00 HATOM 3107 HG11 ILE A1169 4.177 5.187 -8.361 1.00 1.00 HATOM 3108 HG12 ILE A1169 4.766 5.923 -6.815 1.00 1.00 H
ATOM 3109 HD11 ILE A1169 6.812 5.053 -8.122 1.00 1.00 HATOM 3110 HD12 ILE A1169 6.451 4.017 -6.729 1.00 1.00 HATOM 3111 HD13 ILE A1169 5.863 3.484 -8.316 1.00 1.00 HATOM 3112 HG21 ILE A1169 2.050 5.212 -6.785 1.00 1.00 HATOM 3113 HG22 ILE A1169 2.226 4.020 -8.066 1.00 1.00 HATOM 3114 HG23 ILE A1169 1.664 3.558 -6.460 1.00 1.00 HATOM 3115 HN ILE A1169 2.972 2.173 -4.927 1.00 1.00 HATOM 3116 NPRO A1170 4.421 6.268 -3.897 1.00 1.00 NATOM 3117 CA PRO A1170 3.911 7.236 -2.964 1.00 1.00 CATOM 3118 CPRO A1170 2.816 8.170 -3.446 1.00 1.00 CATOM 3119 OPRO A1170 2.575 8.228 -4.649 1.00 1.00 OATOM 3120 CB PRO A1170 5.195 7.907 -2.452 1.00 1.00 CATOM 3121 CG PRO A1170 6.296 7.468 -3.461 1.00 1.00 CATOM 3122 CD PRO A1170 5.891 6.082 -3.985 1.00 1.00 CATOM 3123 HA PRO A1170 3.514 6.682 -2.109 1.00 1.00 HATOM 3124 HD2 PRO A1170 6.312 5.973 -5.036 1.00 1.00 HATOM 3125 HD1 PRO A1170 6.229 5.253 -3.364 1.00 1.00 HATOM 3126 HG2 PRO A1170 7.327 7.591 -3.033 1.00 1.00 HATOM 3127 HG1 PRO A1170 6.314 8.266 -4.258 1.00 1.00 HATOM 3128 HB1 PRO A1170 5.444 7.577 -1.456 1.00 1.00 HATOM 3129 HB2 PRO A1170 5.091 8.986 -2.344 1.00 1.00 HATOM 3130 NMET A1171 2.179 8.912 -2.480 1.00 1.00 NATOM 3131 CA MET A1171 0.990 9.726 -2.796 1.00 1.00 CATOM 3132 CMET A1171 1.387 11.164 -3.139 1.00 1.00 CATOM 3133 OMET A1171 0.827 11.663 -4.116 1.00 1.00 OATOM 3134 CB MET A1171 -0.004 9.796 -1.621 1.00 1.00 CATOM 3135 CG MET A1171 -0.828 8.521 -1.412 1.00 1.00 CATOM 3136 SD MET A1171 -1.719 8.5810.203 1.00 1.00 SATOM 3137 CE MET A1171 -3.145 9.684 -0.084 1.00 1.00 CATOM 3138 HA MET A1171 0.521 9.314 -3.719 1.00 1.00 HATOM 3139 HB1 MET A1171 -0.712 10.636 -1.706 1.00 1.00 HATOM 3140 HB2 MET A1171 0.563 10.069 -0.701 1.00 1.00 HATOM 3141 HG1 MET A1171 -1.462 8.441 -2.304 1.00 1.00 HATOM 3142 HG2 MET A1171 -0.066 7.689 -1.438 1.00 1.00 HATOM 3143 HE1 MET A1171 -3.724 9.329 -0.914 1.00 1.00 HATOM 3144 HE2 MET A1171 -3.763 9.6650.820 1.00 1.00 HATOM 3145 HE3 MET A1171 -2.803 10.709 -0.281 1.00 1.00 HATOM 3146 HN MET A1171 2.509 8.828 -1.552 1.00 1.00 HATOM 3147 NGLY A1172 2.329 11.774 -2.393 1.00 1.00 NATOM 3148 CA GLY A1172 2.668 13.164 -2.714 1.00 1.00 CATOM 3149 CGLY A1172 3.642 13.127 -3.845 1.00 1.00 CATOM 3150 OGLY A1172 4.832 13.173 -3.542 1.00 1.00 OATOM 3151 HA2 GLY A1172 3.179 13.683 -1.852 1.00 1.00 HATOM 3152 HA1 GLY A1172 1.751 13.780 -2.982 1.00 1.00 HATOM 3153 HN GLY A1172 2.687 11.308 -1.573 1.00 1.00 HATOM 3154 NVAL A1173 3.204 12.975 -5.124 1.00 1.00 NATOM 3155 CA VAL A1173 4.096 12.698 -6.238 1.00 1.00 CATOM 3156 CVAL A1173 3.342 13.296 -7.416 1.00 1.00 CATOM 3157 OVAL A1173 2.566 12.542 -7.993 1.00 1.00 OATOM 3158 CB VAL A1173 4.414 11.165 -6.434 1.00 1.00 CATOM 3159 CG1 VAL A1173 5.480 10.818 -7.518 1.00 1.00 CATOM 3160 CG2 VAL A1173 4.713 10.422 -5.122 1.00 1.00 C
ATOM 3161 HA VAL A1173 5.045 13.230 -6.077 1.00 1.00 HATOM 3162 HB VAL A1173 3.538 10.640 -6.830 1.00 1.00 HATOM 3163 HG11 VAL A1173 5.279 11.300 -8.480 1.00 1.00 HATOM 3164 HG12 VAL A1173 6.477 11.099 -7.196 1.00 1.00 HATOM 3165 HG13 VAL A1173 5.583 9.782 -7.751 1.00 1.00 HATOM 3166 HG21 VAL A1173 5.664 10.652 -4.660 1.00 1.00 HATOM 3167 HG22 VAL A1173 4.815 9.361 -5.393 1.00 1.00 HATOM 3168 HG23 VAL A1173 3.847 10.594 -4.437 1.00 1.00 HATOM 3169 HN VAL A1173 2.233 12.941 -5.343 1.00 1.00 HATOM 3170 NGLY A1174 3.612 14.583 -7.755 1.00 1.00 NATOM 3171 CA GLY A1174 2.895 15.130 -8.888 1.00 1.00 CATOM 3172 CGLY A1174 2.517 14.183 -9.990 1.00 1.00 CATOM 3173 OGLY A1174 1.408 14.146 -10.463 1.00 1.00 OATOM 3174 HA2 GLY A1174 3.622 15.883 -9.311 1.00 1.00 HATOM 3175 HA1 GLY A1174 2.007 15.668 -8.617 1.00 1.00 HATOM 3176 HN GLY A1174 4.223 15.158 -7.199 1.00 1.00 HATOM 3177 NLEU A1175 3.511 13.401 -10.479 1.00 1.00 NATOM 3178 CA LEU A1175 3.265 12.633 -11.697 1.00 1.00 CATOM 3179 CLEU A1175 2.394 11.407 -11.510 1.00 1.00 CATOM 3180 OLEU A1175 1.823 10.940 -12.492 1.00 1.00 OATOM 3181 CB LEU A1175 4.643 12.155 -12.213 1.00 1.00 CATOM 3182 CG LEU A1175 4.680 11.560 -13.666 1.00 1.00 CATOM 3183 CD1 LEU A1175 4.363 12.488 -14.906 1.00 1.00 CATOM 3184 CD2 LEU A1175 6.104 10.909 -13.912 1.00 1.00 CATOM 3185 HA LEU A1175 2.773 13.298 -12.487 1.00 1.00 HATOM 3186 HB1 LEU A1175 4.992 11.389 -11.464 1.00 1.00 HATOM 3187 HB2 LEU A1175 5.305 13.043 -12.255 1.00 1.00 HATOM 3188 HG LEU A1175 3.882 10.763 -13.678 1.00 1.00 HATOM 3189 HD21 LEU A1175 6.277 10.021 -13.225 1.00 1.00 HATOM 3190 HD22 LEU A1175 6.144 10.377 -14.896 1.00 1.00 HATOM 3191 HD23 LEU A1175 6.913 11.585 -13.857 1.00 1.00 HATOM 3192 HD11 LEU A1175 5.142 13.247 -15.051 1.00 1.00 HATOM 3193 HD12 LEU A1175 4.251 11.976 -15.875 1.00 1.00 HATOM 3194 HD13 LEU A1175 3.380 13.035 -14.791 1.00 1.00 HATOM 3195 HN LEU A1175 4.347 13.328 -9.919 1.00 1.00 HATOM 3196 NSER A1176 2.339 10.846 -10.264 1.00 1.00 NATOM 3197 CA SER A1176 1.660 9.550 -10.152 1.00 1.00 CATOM 3198 CSER A1176 0.217 9.484 -10.591 1.00 1.00 CATOM 3199 OSER A1176 -0.074 8.685 -11.460 1.00 1.00 OATOM 3200 CB SER A1176 1.906 8.824 -8.797 1.00 1.00 CATOM 3201 OG SER A1176 1.104 7.640 -8.803 1.00 1.00 OATOM 3202 HA SER A1176 2.180 8.815 -10.873 1.00 1.00 HATOM 3203 HB1 SER A1176 1.496 9.461 -7.997 1.00 1.00 HATOM 3204 HB2 SER A1176 3.033 8.608 -8.590 1.00 1.00 HATOM 3205 HG SER A1176 1.337 7.119 -8.035 1.00 1.00 HATOM 3206 HN SER A1176 2.777 11.263 -9.456 1.00 1.00 HATOM 3207 NPRO A1177 -0.745 10.235 -10.022 1.00 1.00 NATOM 3208 CA PRO A1177 -2.120 10.188 -10.541 1.00 1.00 CATOM 3209 CP ROA 1177 -2.261 10.821 -11.925 1.00 1.00 CATOM 3210 OPRO A1177 -3.320 10.640 -12.518 1.00 1.00 OATOM 3211 CB PRO A1177 -2.813 11.110 -9.429 1.00 1.00 CATOM 3212 CG PRO A1177 -1.688 12.098 -9.063 1.00 1.00 C
ATOM 3213 CD PRO A1177 -0.516 11.097 -8.876 1.00 1.00CATOM 3214 HA PRO A1177 -2.484 9.178 -10.593 1.00 1.00HATOM 3215 HD2 PRO A1177 0.451 11.687 -8.839 1.00 1.00HATOM 3216 HD1 PRO A1177 -0.674 10.536 -7.949 1.00 1.00HATOM 3217 HG2 PRO A1177 -1.946 12.562 -8.162 1.00 1.00HATOM 3218 HG1 PRO A1177 -1.439 12.829 -9.865 1.00 1.00HATOM 3219 HB1 PRO A1177 -3.011 10.425 -8.560 1.00 1.00HATOM 3220 HB2 PRO A1177 -3.753 11.534 -9.790 1.00 1.00HATOM 3221 NPHE A1178 -1.258 11.499 -12.499 1.00 1.00NATOM 3222 CA PHE A1178 -1.329 12.082 -13.832 1.00 1.00CATOM 3223 CPHE A1178 -1.357 11.000 -14.914 1.00 1.00CATOM 3224 OPHE A1178 -2.038 11.128 -15.904 1.00 1.00OATOM 3225 CB PHE A1178 -0.134 13.002 -14.118 1.00 1.00CATOM 3226 CG PHE A1178 -0.299 13.873 -15.418 1.00 1.00CATOM 3227 CD1 PHE A1178 0.460 13.650 -16.594 1.00 1.00CATOM 3228 CD2 PHE A1178 -1.162 14.965 -15.308 1.00 1.00CATOM 3229 CE1 PHE A1178 0.167 14.402 -17.701 1.00 1.00CATOM 3230 CE2 PHE A1178 -1.355 15.786 -16.410 1.00 1.00CATOM 3231 CZ PHE A1178 -0.695 15.488 -17.610 1.00 1.00CATOM 3232 HA PHE A1178 -2.272 12.713 -13.931 1.00 1.00HATOM 3233 HB1 PHE A1178 0.032 13.693 -13.257 1.00 1.00HATOM 3234 HB2 PHE A1178 0.727 12.348 -14.196 1.00 1.00HATOM 3235 HD2 PHE A1178 -1.614 15.188 -14.373 1.00 1.00HATOM 3236 HE2 PHE A1178 -1.998 16.650 -16.267 1.00 1.00HATOM 3237 HZ PHE A1178 -0.830 16.073 -18.478 1.00 1.00HATOM 3238 HE1 PHE A1178 0.600 14.092 -18.620 1.00 1.00HATOM 3239 HD1 PHE A1178 1.312 12.958 -16.620 1.00 1.00HATOM 3240 HN PHE A1178 -0.418 11.627 -11.948 1.00 1.00HATOM 3241 NLEU A1179 -0.569 9.911 -14.788 1.00 1.00NATOM 3242 CA LEU A1179 -0.665 8.793 -15.707 1.00 1.00CATOM 3243 CLEU A1179 -2.069 8.206 -15.512 1.00 1.00CATOM 3244 OLEU A1179 -2.648 7.740 -16.479 1.00 1.00OATOM 3245 CB LEU A1179 0.464 7.712 -15.544 1.00 1.00CATOM 3246 CG LEU A1179 1.683 8.106 -16.406 1.00 1.00CATOM 3247 CD1 LEU A1179 2.260 9.495 -15.962 1.00 1.00CATOM 3248 CD2 LEU A1179 2.710 6.935 -16.407 1.00 1.00CATOM 3249 HA LEU A1179 -0.660 9.082 -16.776 1.00 1.00HATOM 3250 HB1 LEU A1179 0.746 7.494 -14.476 1.00 1.00HATOM 3251 HB2 LEU A1179 -0.018 6.798 -15.955 1.00 1.00HATOM 3252 HG LEU A1179 1.387 8.184 -17.490 1.00 1.00HATOM 3253 HD21 LEU A1179 2.159 6.072 -16.828 1.00 1.00HATOM 3254 HD22 LEU A1179 3.540 7.195 -17.069 1.00 1.00HATOM 3255 HD23 LEU A1179 2.998 6.713 -15.406 1.00 1.00HATOM 3256 HD11 LEU A1179 2.402 9.459 -14.895 1.00 1.00HATOM 3257 HD12 LEU A1179 1.644 10.340 -16.215 1.00 1.00HATOM 3258 HD13 LEU A1179 3.219 9.656 -16.471 1.00 1.00HATOM 3259 HN LEU A1179 -0.009 9.864 -14.000 1.00 1.00HATOM 3260 NLEU A1180 -2.613 8.208 -14.285 1.00 1.00NATOM 3261 CA LEU A1180 -4.037 7.784 -14.174 1.00 1.00CATOM 3262 CLEU A1180 -5.034 8.684 -14.899 1.00 1.00CATOM 3263 OLEU A1180 -5.938 8.193 -15.557 1.00 1.00OATOM 3264 CB LEU A1180 -4.534 7.537 -12.683 1.00 1.00C
ATOM 3265 CG LEU A1180-3.811 6.465 -11.823 1.00 1.00 CATOM 3266 CD1 LEU A1180-4.282 6.358 -10.318 1.00 1.00 CATOM 3267 CD2 LEU A1180-3.788 5.009 -12.430 1.00 1.00 CATOM 3268 HA LEU A1180-4.072 6.837 -14.711 1.00 1.00 HATOM 3269 HB1 LEU A1180-4.458 8.429 -12.040 1.00 1.00 HATOM 3270 HB2 LEU A1180-5.550 7.253 -12.810 1.00 1.00 HATOM 3271 HG LEU A1180-2.732 6.731 -11.855 1.00 1.00 HATOM 3272 HD21 LEU A1180-3.432 5.014 -13.469 1.00 1.00 HATOM 3273 HD22 LEU A1180-4.768 4.573 -12.517 1.00 1.00 HATOM 3274 HD23 LEU A1180-3.090 4.266 -11.941 1.00 1.00 HATOM 3275 HD11 LEU A1180-3.679 5.633 -9.8261.00 1.00 HATOM 3276 HD12 LEU A1180-5.329 6.150 -10.239 1.00 1.00 HATOM 3277 HD13 LEU A1180-4.110 7.309 -9.8101.00 1.00 HATOM 3278 HN LEU A1180-2.102 8.439 -13.414 1.00 1.00 HATOM 3279 NALA A1181-4.891 10.018 -14.689 1.00 1.00 NATOM 3280 CA ALA A1181-5.698 10.967 -15.460 1.00 1.00 CATOM 3281 CALA A1181-5.498 10.776 -16.983 1.00 1.00 CATOM 3282 OALA A1181-6.493 10.675 -17.702 1.00 1.00 OATOM 3283 CB ALA A1181-5.324 12.459 -15.130 1.00 1.00 CATOM 3284 HA ALA A1181-6.724 10.795 -15.240 1.00 1.00 HATOM 3285 HB1 ALA A1181-5.562 12.531 -14.062 1.00 1.00 HATOM 3286 HB2 ALA A1181-4.276 12.759 -15.337 1.00 1.00 HATOM 3287 HB3 ALA A1181-6.001 13.098 -15.681 1.00 1.00 HATOM 3288 HN ALA A1181-4.148 10.358 -14.143 1.00 1.00 HATOM 3289 NGLN A1182-4.236 10.767 -17.521 1.00 1.00 NATOM 3290 CA GLN A1182-4.072 10.684 -18.980 1.00 1.00 CATOM 3291 CGLN A1182-4.770 9.404 -19.366 1.00 1.00 CATOM 3292 OGLN A1182-5.570 9.338 -20.286 1.00 1.00 OATOM 3293 CB GLN A1182-2.595 10.644 -19.394 1.00 1.00 CATOM 3294 CG GLN A1182-1.900 12.036 -19.233 1.00 1.00 CATOM 3295 CD GLN A1182-0.420 11.888 -19.533 1.00 1.00 CATOM 3296 OE1 GLN A1182 0.256 11.016 -19.029 1.00 1.00 OATOM 3297 NE2 GLN A1182 0.145 12.691 -20.456 1.00 1.00 NATOM 3298 HA GLN A1182-4.593 11.604 -19.352 1.00 1.00 HATOM 3299 HB1 GLN A1182-2.577 10.511 -20.482 1.00 1.00 HATOM 3300 HB2 GLN A1182-2.100 9.845 -18.806 1.00 1.00 HATOM 3301 HG1 GLN A1182-2.302 12.787 -19.978 1.00 1.00 HATOM 3302 HG2 GLN A1182-1.942 12.444 -18.235 1.00 1.00 HATOM 3303 HE22 GLN A1182 1.074 12.556 -20.747 1.00 1.00 HATOM 3304 HE21 GLN A1182-0.324 13.479 -20.830 1.00 1.00 HATOM 3305 HN GLN A1182-3.486 10.925 -16.924 1.00 1.00 HATOM 3306 NPHE A1183-4.399 8.287 -18.665 1.00 1.00 NATOM 3307 CA PHE A1183-5.062 6.974 -18.909 1.00 1.00 CATOM 3308 CPHE A1183-6.541 7.137 -18.907 1.00 1.00 CATOM 3309 OPHE A1183-7.202 6.566 -19.764 1.00 1.00 OATOM 3310 CB PHE A1183-4.538 5.902 -17.902 1.00 1.00 CATOM 3311 CG PHE A1183-5.395 4.618 -17.982 1.00 1.00 CATOM 3312 CD1 PHE A1183-6.258 4.282 -16.943 1.00 1.00 CATOM 3313 CD2 PHE A1183-5.276 3.769 -19.099 1.00 1.00 CATOM 3314 CE1 PHE A1183-7.031 3.094 -17.033 1.00 1.00 CATOM 3315 CE2 PHE A1183-5.950 2.566 -19.142 1.00 1.00 CATOM 3316 CZ PHE A1183-6.880 2.260 -18.124 1.00 1.00 C
ATOM 3317 HA PHE A1183 -4.771 6.684 -19.899 1.00 1.00 HATOM 3318 HB1 PHE A1183 -4.724 6.417 -16.942 1.00 1.00 HATOM 3319 HB2 PHE A1183 -3.450 5.623 -17.993 1.00 1.00 HATOM 3320 HD2 PHE A1183 -4.615 4.162 -19.891 1.00 1.00 HATOM 3321 HE2 PHE A1183 -5.766 1.920 -19.960 1.00 1.00 HATOM 3322 HZ PHE A1183 -7.530 1.416 -18.276 1.00 1.00 HATOM 3323 HE1 PHE A1183 -7.689 2.776 -16.268 1.00 1.00 HATOM 3324 HD1 PHE A1183 -6.334 4.896 -16.052 1.00 1.00 HATOM 3325 HN PHE A1183 -3.714 8.346 -17.953 1.00 1.00 HATOM 3326 NTHR A1184 -7.206 7.838 -17.954 1.00 1.00 NATOM 3327 CA THR A1184 -8.657 7.971 -18.080 1.00 1.00 CATOM 3328 CTHR A1184 -8.894 8.636 -19.451 1.00 1.00 CATOM 3329 OTHR A1184 -9.716 8.064 -20.128 1.00 1.00 OATOM 3330 CB THR A1184 -9.194 8.817 -16.920 1.00 1.00 CATOM 3331 OG1 THR A1184 -8.664 8.195 -15.711 1.00 1.00 OATOM 3332 CG2 THR A1184 -10.727 8.690 -16.781 1.00 1.00 CATOM 3333 HA THR A1184 -9.062 6.947 -18.125 1.00 1.00 HATOM 3334 HB THR A1184 -8.876 9.814 -16.974 1.00 1.00 HATOM 3335 HG1 THR A1184 -8.924 8.523 -14.865 1.00 1.00 HATOM 3336 HG23 THR A1184 -11.203 9.157 -17.692 1.00 1.00 HATOM 3337 HG21 THR A1184 -11.028 7.646 -16.673 1.00 1.00 HATOM 3338 HG22 THR A1184 -11.152 9.189 -15.886 1.00 1.00 HATOM 3339 HN THR A1184 -6.686 8.304 -17.178 1.00 1.00 HATOM 3340 NSER A1185 -8.197 9.701 -19.929 1.00 1.00 NATOM 3341 CA SER A1185 -8.305 10.134 -21.329 1.00 1.00 CATOM 3342 CSER A1185 -8.169 8.924 -22.214 1.00 1.00 CATOM 3343 OSER A1185 -8.959 8.780 -23.130 1.00 1.00 OATOM 3344 CB SER A1185 -7.374 11.293 -21.780 1.00 1.00 CATOM 3345 OG SER A1185 -7.759 11.902 -23.026 1.00 1.00 OATOM 3346 HA SER A1185 -9.290 10.592 -21.405 1.00 1.00 HATOM 3347 HB1 SER A1185 -6.338 10.918 -21.845 1.00 1.00 HATOM 3348 HB2 SER A1185 -7.420 12.054 -20.980 1.00 1.00 HATOM 3349 HG SER A1185 -7.701 11.226 -23.703 1.00 1.00 HATOM 3350 HN SER A1185 -7.517 10.113 -19.342 1.00 1.00 HATOM 3351 NALA A1186 -7.164 8.065 -22.049 1.00 1.00 NATOM 3352 CA ALA A1186 -7.202 6.908 -22.915 1.00 1.00 CATOM 3353 CALA A1186 -8.516 6.123 -22.766 1.00 1.00 CATOM 3354 OALA A1186 -8.882 5.571 -23.815 1.00 1.00 OATOM 3355 CB ALA A1186 -5.896 6.083 -22.759 1.00 1.00 CATOM 3356 HA ALA A1186 -7.242 7.260 -24.002 1.00 1.00 HATOM 3357 HB1 ALA A1186 -5.760 5.404 -23.603 1.00 1.00 HATOM 3358 HB2 ALA A1186 -5.046 6.762 -22.634 1.00 1.00 HATOM 3359 HB3 ALA A1186 -6.003 5.552 -21.816 1.00 1.00 HATOM 3360 HN ALA A1186 -6.532 8.152 -21.311 1.00 1.00 HATOM 3361 NILE A1187 -9.211 6.080 -21.634 1.00 1.00 NATOM 3362 CA ILE A1187 -10.563 5.485 -21.655 1.00 1.00 CATOM 3363 CILE A1187 -11.561 6.268 -22.453 1.00 1.00 CATOM 3364 OILE A1187 -12.392 5.691 -23.134 1.00 1.00 OATOM 3365 CB ILE A1187 -11.103 5.086 -20.269 1.00 1.00 CATOM 3366 CG1 ILE A1187 -10.144 4.114 -19.474 1.00 1.00 CATOM 3367 CG2 ILE A1187 -12.516 4.434 -20.397 1.00 1.00 CATOM 3368 CD1 ILE A1187 -9.448 2.959 -20.316 1.00 1.00 C
ATOM 3369 HA ILE A1187 -10.469 4.606 -22.238 1.00 1.00 HATOM 3370 HB ILE A1187 -11.290 5.966 -19.643 1.00 1.00 HATOM 3371 HG11 ILE A1187 -9.3124.745 -19.122 1.00 1.00 HATOM 3372 HG12 ILE A1187 -10.591 3.726 -18.568 1.00 1.00 HATOM 3373 HD11 ILE A1187 -10.181 2.383 -20.916 1.00 1.00 HATOM 3374 HD12 ILE A1187 -8.6153.404 -20.925 1.00 1.00 HATOM 3375 HD13 ILE A1187 -9.0112.278 -19.608 1.00 1.00 HATOM 3376 HG21 ILE A1187 -12.527 3.643 -21.168 1.00 1.00 HATOM 3377 HG22 ILE A1187 -12.847 3.922 -19.424 1.00 1.00 HATOM 3378 HG23 ILE A1187 -13.271 5.202 -20.697 1.00 1.00 HATOM 3379 HN ILE A1187 -8.8486.524 -20.804 1.00 1.00 HATOM 3380 NCYS A1188 -11.446 7.611 -22.353 1.00 1.00 NATOM 3381 CA CYS A1188 -12.216 8.460 -23.238 1.00 1.00 CATOM 3382 CCYS A1188 -12.107 7.883 -24.603 1.00 1.00 CATOM 3383 OCYS A1188 -13.097 7.644 -25.280 1.00 1.00 OATOM 3384 CB CYS A1188 -11.623 9.879 -23.343 1.00 1.00 CATOM 3385 SG CYS A1188 -12.756 11.068 -24.162 1.00 1.00 SATOM 3386 HA CYS A1188 -13.264 8.490 -22.934 1.00 1.00 HATOM 3387 HB1 CYS A1188 -11.440 10.249 -22.315 1.00 1.00 HATOM 3388 HB2 CYS A1188 -10.671 9.976 -23.923 1.00 1.00 HATOM 3389 HG CYS A1188 -12.108 11.830 -24.258 1.00 1.00 HATOM 3390 HN CYS A1188 -10.808 7.988 -21.671 1.00 1.00 HATOM 3391 NSER A1189 -10.835 7.543 -25.027 1.00 1.00 NATOM 3392 CA SER A1189 -10.685 7.039 -26.408 1.00 1.00 CATOM 3393 CSER A1189 -11.465 5.739 -26.573 1.00 1.00 CATOM 3394 OSER A1189 -12.279 5.676 -27.495 1.00 1.00 OATOM 3395 CB SER A1189 -9.1986.815 -26.826 1.00 1.00 CATOM 3396 OG SER A1189 -8.5015.670 -26.365 1.00 1.00 OATOM 3397 HA SER A1189 -11.134 7.804 -27.138 1.00 1.00 HATOM 3398 HB1 SER A1189 -9.1736.636 -27.942 1.00 1.00 HATOM 3399 HB2 SER A1189 -8.6387.705 -26.512 1.00 1.00 HATOM 3400 HG SER A1189 -8.3755.667 -25.431 1.00 1.00 HATOM 3401 HN SER A1189 -9.9757.671 -24.485 1.00 1.00 HATOM 3402 NVAL A1190 -11.185 4.677 -25.795 1.00 1.00 NATOM 3403 CA VAL A1190 -11.822 3.361 -26.161 1.00 1.00 CATOM 3404 CVAL A1190 -13.394 3.508 -25.977 1.00 1.00 CATOM 3405 OVAL A1190 -14.209 2.963 -26.739 1.00 1.00 OATOM 3406 CB VAL A1190 -11.165 2.069 -25.530 1.00 1.00 CATOM 3407 CG1 VAL A1190 -9.6781.848 -25.884 1.00 1.00 CATOM 3408 CG2 VAL A1190 -11.343 1.874 -24.045 1.00 1.00 CATOM 3409 HA VAL A1190 -11.695 3.271 -27.259 1.00 1.00 HATOM 3410 HB VAL A1190 -11.687 1.228 -25.938 1.00 1.00 HATOM 3411 HG11 VAL A1190 -9.0912.637 -25.395 1.00 1.00 HATOM 3412 HG12 VAL A1190 -9.4821.923 -26.980 1.00 1.00 HATOM 3413 HG13 VAL A1190 -9.2700.885 -25.560 1.00 1.00 HATOM 3414 HG21 VAL A1190 -11.063 0.864 -23.686 1.00 1.00 HATOM 3415 HG22 VAL A1190 -10.704 2.616 -23.553 1.00 1.00 HATOM 3416 HG23 VAL A1190 -12.401 2.094 -23.724 1.00 1.00 HATOM 3417 HN VAL A1190 -10.519 4.707 -25.008 1.00 1.00 HATOM 3418 NVAL A1191 -13.827 4.243 -24.916 1.00 1.00 NATOM 3419 CA VAL A1191 -15.254 4.468 -24.789 1.00 1.00 CATOM 3420 CVAL A1191 -15.897 5.198 -25.961 1.00 1.00 C
ATOM 3421 OVAL A1191 -16.947 4.782 -26.497 1.00 1.00OATOM 3422 CB VAL A1191 -15.551 5.099 -23.406 1.00 1.00CATOM 3423 CG1 VAL A1191 -16.936 5.890 -23.317 1.00 1.00CATOM 3424 CG2 VAL A1191 -15.495 3.988 -22.317 1.00 1.00CATOM 3425 HA VAL A1191 -15.850 3.558 -24.721 1.00 1.00HATOM 3426 HB VAL A1191 -14.794 5.912 -23.161 1.00 1.00HATOM 3427 HG11 VAL A1191 -16.824 6.849 -23.917 1.00 1.00HATOM 3428 HG12 VAL A1191 -17.774 5.331 -23.736 1.00 1.00HATOM 3429 HG13 VAL A1191 -17.190 6.153 -22.291 1.00 1.00HATOM 3430 HG21 VAL A1191 -16.396 3.364 -22.416 1.00 1.00HATOM 3431 HG22 VAL A1191 -14.646 3.289 -22.345 1.00 1.00HATOM 3432 HG23 VAL A1191 -15.513 4.452 -21.330 1.00 1.00HATOM 3433 HN VAL A1191 -13.191 4.551 -24.226 1.00 1.00HATOM 3434 NARG A1192 -15.250 6.282 -26.470 1.00 1.00NATOM 3435 CA ARG A1192 -15.726 6.827 -27.730 1.00 1.00CATOM 3436 CARG A1192 -15.679 5.712 -28.759 1.00 1.00CATOM 3437 OARG A1192 -16.673 5.468 -29.428 1.00 1.00OATOM 3438 CB ARG A1192 -14.873 8.047 -28.215 1.00 1.00CATOM 3439 CG ARG A1192 -15.549 9.379 -27.669 1.00 1.00CATOM 3440 CD ARG A1192 -15.695 9.449 -26.156 1.00 1.00CATOM 3441 NE ARG A1192 -16.339 10.708 -25.746 1.00 1.00NATOM 3442 CZ ARG A1192 -16.450 11.075 -24.490 1.00 1.00CATOM 3443 NH1 ARG A1192 -15.995 10.342 -23.494 1.00 1.00NATOM 3444 NH2 ARG A1192 -17.078 12.235 -24.233 1.00 1.00NATOM 3445 HA ARG A1192 -16.798 7.060 -27.583 1.00 1.00HATOM 3446 HB1 ARG A1192 -14.922 8.121 -29.308 1.00 1.00HATOM 3447 HB2 ARG A1192 -13.848 7.987 -27.883 1.00 1.00HATOM 3448 HG1 ARG A1192 -14.915 10.220 -28.088 1.00 1.00HATOM 3449 HG2 ARG A1192 -16.535 9.521 -28.086 1.00 1.00HATOM 3450 HD1 ARG A1192 -16.335 8.652 -25.819 1.00 1.00HATOM 3451 HD2 ARG A1192 -14.694 9.230 -25.763 1.00 1.00HATOM 3452 HE ARG A1192 -16.697 11.317 -26.474 1.00 1.00HATOM 3453 HH12 ARG A1192 -16.032 10.720 -22.511 1.00 1.00HATOM 3454 HH11 ARG A1192 -15.539 9.450 -23.619 1.00 1.00HATOM 3455 HH22 ARG A1192 -17.255 12.515 -23.248 1.00 1.00HATOM 3456 HH21 ARG A1192 -17.466 12.806 -24.972 1.00 1.00HATOM 3457 HN ARG A1192 -14.416 6.686 -26.038 1.00 1.00HATOM 3458 NARG A1193 -14.568 4.990 -28.979 1.00 1.00NATOM 3459 CA ARG A1193 -14.596 3.880 -29.899 1.00 1.00CATOM 3460 CARG A1193 -15.880 3.087 -29.744 1.00 1.00CATOM 3461 OARG A1193 -16.593 2.807 -30.694 1.00 1.00OATOM 3462 CB ARG A1193 -13.390 2.965 -29.795 1.00 1.00CATOM 3463 CG ARG A1193 -13.343 1.980 -31.031 1.00 1.00CATOM 3464 CD ARG A1193 -14.035 0.557 -30.871 1.00 1.00CATOM 3465 NE ARG A1193 -13.357 -0.155 -29.803 1.00 1.00NATOM 3466 CZ ARG A1193 -13.643 -1.376 -29.408 1.00 1.00CATOM 3467 NH1 ARG A1193 -14.612 -2.083 -29.853 1.00 1.00NATOM 3468 NH2 ARG A1193 -12.936 -1.832 -28.418 1.00 1.00NATOM 3469 HA ARG A1193 -14.545 4.332 -30.868 1.00 1.00HATOM 3470 HB1 ARG A1193 -13.376 2.389 -28.841 1.00 1.00HATOM 3471 HB2 ARG A1193 -12.478 3.556 -29.845 1.00 1.00HATOM 3472 HG1 ARG A1193 -13.751 2.467 -31.935 1.00 1.00H
ATOM 3473 HG2 ARG A1193 -12.306 1.702 -31.354 1.00 1.00HATOM 3474 HD1 ARG A1193 -15.089 0.762 -30.678 1.00 1.00HATOM 3475 HD2 ARG A1193 -13.982 0.105 -31.883 1.00 1.00HATOM 3476 HE ARG A1193 -12.508 0.319 -29.393 1.00 1.00HATOM 3477 HH12 ARG A1193 -14.756 -3.062 -29.561 1.00 1.00HATOM 3478 HH11 ARG A1193 -15.241 -1.746 -30.595 1.00 1.00HATOM 3479 HH22 ARG A1193 -13.075 -2.780 -28.063 1.00 1.00HATOM 3480 HH21 ARG A1193 -12.175 -1.345 -27.983 1.00 1.00HATOM 3481 HN ARG A1193 -13.773 5.114 -28.364 1.00 1.00HATOM 3482 NALA A1194 -16.257 2.756 -28.480 1.00 1.00NATOM 3483 CA ALA A1194 -17.617 2.074 -28.302 1.00 1.00CATOM 3484 CALA A1194 -17.498 0.563 -28.547 1.00 1.00CATOM 3485 OALA A1194 -16.460 0.073 -28.977 1.00 1.00OATOM 3486 CB ALA A1194 -18.799 2.646 -29.140 1.00 1.00CATOM 3487 HA ALA A1194 -17.873 2.269 -27.238 1.00 1.00HATOM 3488 HB1 ALA A1194 -18.869 2.258 -30.180 1.00 1.00HATOM 3489 HB2 ALA A1194 -19.813 2.425 -28.651 1.00 1.00HATOM 3490 HB3 ALA A1194 -18.732 3.737 -29.285 1.00 1.00HATOM 3491 HN ALA A1194 -15.703 2.951 -27.674 1.00 1.00HATOM 3492 NPHE A1195 -18.560 -0.261 -28.214 1.00 1.00NATOM 3493 CA PHE A1195 -18.399 -1.706 -28.289 1.00 1.00CATOM 3494 CPHE A1195 -19.735 -2.324 -28.776 1.00 1.00CATOM 3495 OPHE A1195 -20.682 -1.545 -28.741 1.00 1.00OATOM 3496 CB PHE A1195 -17.977 -2.282 -26.922 1.00 1.00CATOM 3497 CG PHE A1195 -16.938 -1.333 -26.221 1.00 1.00CATOM 3498 CD1 PHE A1195 -15.573 -1.523 -26.421 1.00 1.00CATOM 3499 CD2 PHE A1195 -17.383 -0.307 -25.358 1.00 1.00CATOM 3500 CE1 PHE A1195 -14.668 -0.618 -25.868 1.00 1.00CATOM 3501 CE2 PHE A1195 -16.484 0.598 -24.792 1.00 1.00CATOM 3502 CZ PHE A1195 -15.110 0.400 -25.046 1.00 1.00CATOM 3503 HA PHE A1195 -17.661 -1.974 -29.031 1.00 1.00HATOM 3504 HB1 PHE A1195 -17.478 -3.255 -27.117 1.00 1.00HATOM 3505 HB2 PHE A1195 -18.850 -2.480 -26.238 1.00 1.00HATOM 3506 HD2 PHE A1195 -18.462 -0.175 -25.256 1.00 1.00HATOM 3507 HE2 PHE A1195 -16.800 1.401 -24.164 1.00 1.00HATOM 3508 HZ PHE A1195 -14.384 1.013 -24.458 1.00 1.00HATOM 3509 HE1 PHE A1195 -13.607 -0.660 -26.032 1.00 1.00HATOM 3510 HD1 PHE A1195 -15.190 -2.423 -26.968 1.00 1.00HATOM 3511 HN PHE A1195 -19.436 0.091 -27.783 1.00 1.00HATOM 3512 NPRO A1196 -19.889 -3.623 -29.149 1.00 1.00NATOM 3513 CA PRO A1196 -21.176 -4.038 -29.691 1.00 1.00CATOM 3514 CPRO A1196 -22.305 -3.987 -28.726 1.00 1.00CATOM 3515 OPRO A1196 -23.396 -3.572 -29.083 1.00 1.00OATOM 3516 CB PRO A1196 -20.820 -5.541 -30.052 1.00 1.00CATOM 3517 CG PRO A1196 -19.308 -5.478 -30.296 1.00 1.00CATOM 3518 CD PRO A1196 -18.794 -4.545 -29.200 1.00 1.00CATOM 3519 HA PRO A1196 -21.426 -3.486 -30.561 1.00 1.00HATOM 3520 HD2 PRO A1196 -18.611 -5.023 -28.224 1.00 1.00HATOM 3521 HD1 PRO A1196 -17.794 -4.228 -29.613 1.00 1.00HATOM 3522 HG2 PRO A1196 -19.207 -4.978 -31.293 1.00 1.00HATOM 3523 HG1 PRO A1196 -18.826 -6.457 -30.257 1.00 1.00HATOM 3524 HB1 PRO A1196 -21.382 -5.871 -30.949 1.00 1.00H
ATOM 3525 HB2 PRO A1196 -21.036 -6.220 -29.237 1.00 1.00 HATOM 3526 NHIE A1197 -22.078 -4.442 -27.474 1.00 1.00 NATOM 3527 CA HIE A1197 -23.163 -4.316 -26.461 1.00 1.00 CATOM 3528 CHIE A1197 -22.525 -4.223 -25.102 1.00 1.00 CATOM 3529 OHIE A1197 -23.027 -4.857 -24.182 1.00 1.00 OATOM 3530 HHIE A1197 -21.171 -4.796 -27.220 1.00 1.00 HATOM 3531 CB HIE A1197 -24.141 -5.461 -26.532 1.00 1.00 CATOM 3532 HB2 HIE A1197 -24.570 -5.524 -27.564 1.00 1.00 HATOM 3533 CG HIE A1197 -23.424 -6.734 -26.316 1.00 1.00 CATOM 3534 ND1 HIE A1197 -23.250 -7.356 -25.037 1.00 1.00 NATOM 3535 CD2 HIE A1197 -22.820 -7.582 -27.164 1.00 1.00 CATOM 3536 HA HIE A1197 -23.747 -3.431 -26.668 1.00 1.00 HATOM 3537 CE1 HIE A1197 -22.502 -8.388 -25.196 1.00 1.00 CATOM 3538 NE2 HIE A1197 -22.223 -8.522 -26.448 1.00 1.00 NATOM 3539 HB1 HIE A1197 -25.035 -5.359 -25.845 1.09 1.00 HATOM 3540 HD2 HIE A1197 -22.734 -7.423 -28.264 1.00 1.00 HATOM 3541 HE1 HIE A1197 -22.213 -9.064 -24.447 1.00 1.00 HATOM 3542 HE2 HIE A1197 -21.625 -9.305 -26.817 1.00 1.00 HATOM 3543 NCYS A1198 -21.375 -3.527 -24.896 1.00 1.00 NATOM 3544 CA CYS A1198 -20.612 -3.835 -23.683 1.00 1.00 CATOM 3545 CCYS A1198 -19.834 -2.604 -23.272 1.00 1.00 CATOM 3546 OCYS A1198 -18.658 -2.432 -23.519 1.00 1.00 OATOM 3547 CB CYS A1198 -19.579 4.959 -23.925 1.00 1.00 CATOM 3548 SG CYS A1198 -20.399 -6.526 -24.173 1.00 1.00 SATOM 3549 HA CYS A1198 -21.265 -4.089 -22.839 1.00 1.00 HATOM 3550 H31 CYS A1198 -18.900 4.851 -24.759 1.00 1.00 HATOM 3551 HB2 CYS A1198 -18.995 -5.076 -23.013 1.00 1.00 HATOM 3552 HG CYS A1198 -19.595 -7.081 -24.483 1.00 1.00 HATOM 3553 HN CYS A1198 -21.041 -2.893 -25.587 1.00 1.00 HATOM 3554 NLEU A1199 -20.546 -1.672 -22.546 1.00 1.00 NATOM 3555 CA LEU A1199 -19.927 -0.417 -22.072 1.00 1.00 CATOM 3556 CLEU A1199 -19.363 -0.595 -20.665 1.00 1.00 CATOM 3557 OLEU A1199 -19.752 -1.550 -20.030 1.00 1.00 OATOM 3558 CB LEU A1199 -21.069 0.679 -22.196 1.00 1.00 CATOM 3559 CG LEU A1199 -20.728 2.186 -21.929 1.90 1.00 CATOM 3560 CD1 LEU A1199 -19.671 2.733 -22.942 1.00 1.00 CATOM 3561 CD2 LEU A1199 -22.051 2.988 -22.149 1.00 1.00 CATOM 3562 HA LEU A1199 -19.044 -0.102 -22.683 1.00 1.00 HATOM 3563 HB1 LEU A1199 -21.956 0.405 -21.562 1.00 1.00 HATOM 3564 HB2 LEU A1199 -21.378 0.575 -23.277 1.00 1.00 HATOM 3565 HG LEU A1199 -20.299 2.407 -20.937 1.00 1.00 HATOM 3566 HD21 LEU A1199 -22.429 2.870 -23.193 1.00 1.00 HATOM 3567 HD22 LEU A1199 -22.856 2.688 -21.456 1.00 1.00 HATOM 3568 HD23 LEU A1199 -21.815 4.092 -22.004 1.00 1.00 HATOM 3569 HD11 LEU A1199 -18.670 2.336 -22.709 1.00 1.00 HATOM 3570 HD12 LEU A1199 -20.004 2.447 -23.915 1.00 1.00 HATOM 3571 HD13 LEU A1199 -19.575 3.821 -23.029 1.00 1.00 HATOM 3572 HN LEU A1199 -21.514 -1.853 -22.370 1.00 1.00 HATOM 3573 NALA A1200 -18.508 0.358 -20.172 1.00 1.00 NATOM 3574 CA ALA A1200 -17.935 0.285 -18.812 1.00 1.00 CATOM 3575 CALA A1200 -17.362 1.605 -18.373 1.00 1.00 CATOM 3576 OALA A1200 -17.255 2.446 -19.209 1.00 1.00 O
ATOM 3577 CB ALA A1200 -16.882 -0.845 -18.951 1.00 1.00CATOM 3578 HA ALA A1200 -18.705 0.058 -18.072 1.00 1.00HATOM 3579 H31 ALA A1200 -17.264 -1.761 -19.432 1.00 1.00HATOM 3580 HB2 ALA A1200 -16.063 -0.387 -19.533 1.00 1.00HATOM 3581 HB3 ALA A1200 -16.439 -1.125 -17.944 1.00 1.00HATOM 3582 HN ALA A1200 -18.212 1.152 -20.718 1.00 1.00HATOM 3583 N PHE A1201 -16.915 1.804 -17.136 1.00 1.00NATOM 3584 CA PHE A1201 -16.267 3.080 -16.850 1.00 1.00CATOM 3585 C PHE A1201 -15.223 3.098 -15.749 1.00 1.00CATOM 3586 O PHE A1201 -15.128 2.054 -15.148 1.00 1.00OATOM 3587 CB PHE A1201 -17.316 4.155 -16.454 1.00 1.00CATOM 3588 CG PHE A1201 -18.303 4.433 -17.577 1.00 1.00CATOM 3589 CD1 PHE A1201 -19.578 3.908 -17.584 1.00 1.00CATOM 3590 CD2 PHE A1201 -17.953 5.341 -18.565 1.00 1.00CATOM 3591 CE1 PHE A1201 -20.545 4.446 -18.433 1.00 1.00CATOM 3592 CE2 PHE A1201 -18.895 5.832 -19.470 1.00 1.00CATOM 3593 CZ PHE A1201 -20.224 5.416 -19.378 1.00 1.00CATOM 3594 HA PHE A1201 -15.733 3.356 -17.734 1.00 1.00HATOM 3595 HB1 PHE A1201 -16.872 5.092 -16.152 1.00 1.00HATOM 3596 HB2 PHE A1201 -17.944 3.787 -15.586 1.00 1.00HATOM 3597 HD2 PHE A1201 -16.909 5.710 -18.596 1.00 1.00HATOM 3598 HE2 PHE A1201 -18.657 6.564 -20.245 1.00 1.00HATOM 3599 HZ PHE A1201 -20.973 5.730 -20.071 1.00 1.00HATOM 3600 HE1 PHE A1201 -21.567 4.033 -18.444 1.00 1.00HATOM 3601 HD1 PHE A1201 -19.861 3.123 -16.898 1.00 1.00HATOM 3602 HN PHE A1201 -16.914 1.057 -16.481 1.00 1.00HATOM 3603 N SER A1202 -14.438 4.188 -15.677 1.00 1.00NATOM 3604 CA SER A1202 -13.332 4.241 -14.674 1.00 1.00CATOM 3605 C SER A1202 -12.951 5.596 -14.067 1.00 1.00CATOM 3606 O SER A1202 -13.123 6.592 -14.762 1.00 1.00OATOM 3607 CB SER A1202 -12.054 3.592 -15.239 1.00 1.00CATOM 3608 OG SER A1202 -11.574 4.218 -16.422 1.00 1.00OATOM 3609 HA SER A1202 -13.644 3.666 -13.783 1.00 1.00HATOM 3610 HB1 SER A1202 -12.310 2.549 -15.484 1.00 1.00HATOM 3611 HB2 SER A1202 -11.225 3.618 -14.542 1.00 1.00HATOM 3612 HG SER A1202 -11.198 5.049 -16.215 1.00 1.00HATOM 3613 HN SER A1202 -14.535 4.896 -16.380 1.00 1.00HATOM 3614 N TYR A1203 -12.471 5.610 -12.807 1.00 1.00NATOM 3615 CA TYR A1203 -12.058 6.860 -12.104 1.00 1.00CATOM 3616 C TYR A1203 -10.901 6.554 -11.119 1.00 1.00CATOM 3617 O TYR A1203 -11.206 6.213 -10.025 1.00 1.00OATOM 3618 CB TYR A1203 -13.288 7.487 -11.427 1.00 1.00CATOM 3619 CG TYR A1203 -13.038 8.955 -11.074 1.00 1.00CATOM 3620 CD1 TYR A1203 -13.544 10.001 -11.838 1.00 1.00CATOM 3621 CD2 TYR A1203 -12.283 9.319 -9.944 1.00 1.00CATOM 3622 CE1 TYR A1203 -13.382 11.334 -11.478 1.00 1.00CATOM 3623 CE2 TYR A1203 -12.037 10.668 -9.601 1.00 1.00CATOM 3624 CZ TYR A1203 -12.682 11.647 -10.342 1.00 1.00CATOM 3625 OH TYR A1203 -12.600 12.962 -9.950 1.00 1.00OATOM 3626 HA TYR A1203 -11.655 7.548 -12.870 1.00 1.00HATOM 3627 HB2 TYR A1203 -13.602 7.001 -10.516 1.00 1.00HATOM 3628 HB1 TYR A1203 -14.110 7.472 -12.193 1.00 1.00H
ATOM 3629 HD2 TYR A1203 -11.845 8.575 -9.348 1.00 1.00 HATOM 3630 HE2 TYR A1203 -11.419 10.924 -8.778 1.00 1.00 HATOM 3631 HE1 TYR A1203 -13.707 12.091 -12.169 1.00 1.00 HATOM 3632 HD1 TYR A1203 -14.055 9.777 -12.791 1.00 1.00 HATOM 3633 HH TYR A1203 -11.882 13.224 -9.357 1.00 1.00 HATOM 3634 HN TYR A1203 -12.352 4.739 -12.277 1.00 1.00 HATOM 3635 N MET A1204 -9.6306.730 -11.455 1.00 1.00 NATOM 3636 CA MET A1204 -8.5116.426 -10.540 1.00 1.00 CATOM 3637 C MET A1204 -8.5774.947 -10.144 1.00 1.00 CATOM 3638 O MET A1204 -8.6054.109 -11.037 1.00 1.00 OATOM 3639 CB MET A1204 -8.5037.545 -9.414 1.00 1.00 CATOM 3640 CG MET A1204 -8.2738.984 -10.029 1.00 1.00 CATOM 3641 SD MET A1204 -6.6949.115 -10.854 1.00 1.00 SATOM 3642 CE MET A1204 -6.78010.947 -11.186 1.00 1.00 CATOM 3643 HA MET A1204 -7.5516.521 -11.013 1.00 1.00 HATOM 3644 HB1 MET A1204 -9.4327.634 -8.938 1.00 1.00 HATOM 3645 HB2 MET A1204 -7.7367.358 -8.605 1.00 1.00 HATOM 3646 HG1 MET A1204 -8.3229.751 -9.231 1.00 1.00 HATOM 3647 HG2 MET A1204 -9.1529.231 -10.665 1.00 1.00 HATOM 3648 HE1 MET A1204 -5.89511.190 -11.714 1.00 1.00 HATOM 3649 HE2 MET A1204 -6.82111.404 -10.174 1.00 1.00 HATOM 3650 HE3 MET A1204 -7.63511.213 -11.826 1.00 1.00 HATOM 3651 HN MET A1204 -9.3626.961 -12.390 1.00 1.00 HATOM 3652 N ASP A1205 -8.5704.530 -8.825 1.00 1.00 NATOM 3653 CA ASP A1205 -8.6413.078 -8.525 1.00 1.00 CATOM 3654 C ASP A1205 -10.081 2.743 -8.380 1.00 1.00 CATOM 3655 O ASP A1205 -10.472 2.137 -7.391 1.00 1.00 OATOM 3656 CB ASP A1205 -7.8452.657 -7.262 1.00 1.00 CATOM 3657 CG ASP A1205 -8.4982.915 -5.861 1.00 1.00 CATOM 3658 OD1 ASP A1205 -9.4203.771 -5.877 1.00 1.00 OATOM 3659 OD2 ASP A1205 -8.1322.302 -4.788 1.00 1.00 OATOM 3660 HA ASP A1205 -8.2172.539 -9.391 1.00 1.00 HATOM 3661 HB1 ASP A1205 -6.8683.189 -7.285 1.00 1.00 HATOM 3662 HB2 ASP A1205 -7.7221.577 -7.352 1.00 1.00 HATOM 3663 HN ASP A1205 -8.6415.187 -8.116 1.00 1.00 HATOM 3664 N ASP A1206 -10.983 3.146 -9.280 1.00 1.00 NATOM 3665 CA ASP A1206 -12.423 2.887 -9.079 1.00 1.00 CATOM 3666 C ASP A1206 -13.199 2.657 -10.343 1.00 1.00 CATOM 3667 O ASP A1206 -13.264 3.418 -11.290 1.00 1.00 OATOM 3668 CB ASP A1206 -13.051 4.057 -8.321 1.00 1.00 CATOM 3669 CG ASP A1206 -12.194 4.197 -7.110 1.00 1.00 CATOM 3670 OD1 ASP A1206 -11.165 4.853 -7.023 1.00 1.00 OATOM 3671 OD2 ASP A1206 -12.455 3.693 -6.027 1.00 1.00 OATOM 3672 HA ASP A1206 -12.539 1.984 -8.437 1.00 1.00 HATOM 3673 HB1 ASP A1206 -14.075 3.751 -7.970 1.00 1.00 HATOM 3674 HB2 ASP A1206 -13.083 5.065 -8.754 1.00 1.00 HATOM 3675 HN ASP A1206 -10.793 3.745 -10.075 1.00 1.00 HATOM 3676 N VAL A1207 -13.866 1.461 -10.432 1.00 1.00 NATOM 3677 CA VAL A1207 -14.365 1.071 -11.762 1.00 1.00 CATOM 3678 C VAL A1207 -15.709 0.400 -11.785 1.00 1.00 CATOM 3679 O VAL A1207 -16.231 0.032 -10.743 1.00 1.00 OATOM 3680 CB VAL A1207 -13.272 0.196 -12.460 1.00 1.00 C
ATOM 3681 CG1 VAL A1207 -11.852 0.794 -12.522 1.00 1.00 CATOM 3682 CG2 VAL A1207 -13.222 -1.198 -11.764 1.00 1.00 CATOM 3683 HA VAL A1207 -14.484 1.969 -12.402 1.00 1.00 HATOM 3684 HB VAL A1207 -13.630 -0.073 -13.461 1.00 1.00 HATOM 3685 HG11 VAL A1207 -11.109 0.164 -13.129 1.00 1.00 HATOM 3686 HG12 VAL A1207 -11.877 1.785 -12.970 1.00 1.00 HATOM 3687 HG13 VAL A1207 -11.441 0.836 -11.503 1.00 1.00 HATOM 3688 HG21 VAL A1207 -14.181 -1.722 -11.773 1.00 1.00 HATOM 3689 HG22 VAL A1207 -12.480 -1.869 -12.206 1.00 1.00 HATOM 3690 HG23 VAL A1207 -12.965 -1.003 -10.741 1.00 1.00 HATOM 3691 HN VAL A1207 -13.953 0.772 -9.706 1.00 1.00 HATOM 3692 NVAL A1208 -16.172 0.324 -13.032 1.00 1.00 NATOM 3693 CA VAL A1208 -17.507 -0.241 -13.314 1.00 1.00 CATOM 3694 CVAL A1208 -17.316 -1.114 -14.525 1.00 1.00 CATOM 3695 OVAL A1208 -17.475 -0.571 -15.619 1.00 1.00 OATOM 3696 CB VAL A1208 -18.550 0.858 -13.611 1.00 1.00 CATOM 3697 CG1 VAL A1208 -19.951 0.316 -13.959 1.00 1.00 CATOM 3698 CG2 VAL A1208 -18.524 1.820 -12.364 1.00 1.00 CATOM 3699 HA VAL A1208 -17.900 -0.832 -12.542 1.00 1.00 HATOM 3700 HB VAL A1208 -18.320 1.547 -14.427 1.00 1.00 HATOM 3701 HG11 VAL A1208 -19.862 -0.484 -14.674 1.00 1.00 HATOM 3702 HG12 VAL A1208 -20.522 -0.035 -13.092 1.00 1.00 HATOM 3703 HG13 VAL A1208 -20.560 1.055 -14.457 1.00 1.00 HATOM 3704 HG21 VAL A1208 -17.590 2.346 -12.267 1.00 1.00 HATOM 3705 HG22 VAL A1208 -19.334 2.594 -12.407 1.00 1.00 HATOM 3706 HG23 VAL A1208 -18.593 1.155 -11.453 1.00 1.00 HATOM 3707 HN VAL A1208 -15.747 0.776 -13.830 1.00 1.00 HATOM 3708 NLEU A1209 -16.991 -2.445 -14.390 1.00 1.00 NATOM 3709 CA LEU A1209 -16.640 -3.307 -15.539 1.00 1.00 CATOM 3710 CLEU A1209 -17.734 -4.275 -15.780 1.00 1.00 CATOM 3711 OLEU A1209 -17.509 -5.470 -15.799 1.00 1.00 OATOM 3712 CB LEU A1209 -15.315 4.011 -15.135 1.00 1.00 CATOM 3713 CG LEU A1209 -14.113 -3.105 -14.851 1.00 1.00 CATOM 3714 CD1 LEU A1209 -12.900 -4.006 -14.431 1.00 1.00 CATOM 3715 CD2 LEU A1209 -13.720 -2.278 -16.078 1.00 1.00 CATOM 3716 HA LEU A1209 -16.504 -2.784 -16.531 1.00 1.00 HATOM 3717 HB1 LEU A1209 -15.105 -4.733 -15.919 1.00 1.00 HATOM 3718 HB2 LEU A1209 -15.465 -4.561 -14.236 1.00 1.00 HATOM 3719 HG LEU A1209 -14.339 -2.417 -14.005 1.00 1.00 HATOM 3720 HD21 LEU A1209 -13.557 -2.816 -17.031 1.00 1.00 HATOM 3721 HD22 LEU A1209 -14.448 -1.525 -16.362 1.00 1.00 HATOM 3722 HD23 LEU A1209 -12.788 -1.701 -15.879 1.00 1.00 HATOM 3723 HD11 LEU A1209 -12.662 -4.766 -15.181 1.00 1.00 HATOM 3724 HD12 LEU A1209 -11.972 -3.436 -14.209 1.00 1.00 HATOM 3725 HD13 LEU A1209 -13.079 -4.665 -13.584 1.00 1.00 HATOM 3726 HN LEU A1209 -16.954 -2.849 -13.492 1.00 1.00 HATOM 3727 NGLY A1210 -18.963 -3.841 -15.957 1.00 1.00 NATOM 3728 CA GLY A1210 -20.053 4.801 -16.265 1.00 1.00 CATOM 3729 CGLY A1210 -20.285 -5.112 -17.679 1.00 1.00 CATOM 3730 OGLY A1210 -21.136 -5.920 -17.933 1.00 1.00 OATOM 3731 HA2 GLY A1210 -21.012 -4.420 -15.929 1.00 1.00 HATOM 3732 HA1 GLY A1210 -19.883 -5.754 -15.749 1.00 1.00 H
ATOM 3733 HN GLY A1210 -19.128 -2.869 -15.942 1.00 1.00HATOM 3734 N ALA A1211 -19.653 -4.494 -18.702 1.00 1.00NATOM 3735 CA ALA A1211 -20.062 -4.863 -20.069 1.00 1.00CATOM 3736 C ALA A1211 -21.578 -4.877 -20.270 1.00 1.00CATOM 3737 O ALA A1211 -22.166 -5.758 -20.873 1.00 1.00OATOM 3738 CB ALA A1211 -19.367 -6.218 -20.343 1.00 1.00CATOM 3739 HA ALA A1211 -19.618 -4.188 -20.795 1.00 1.00HATOM 3740 HB1 ALA A1211 -18.289 -5.957 -20.421 1.00 1.00HATOM 3741 HB2 ALA A1211 -19.420 -6.961 -19.516 1.00 1.00HATOM 3742 HB3 ALA A1211 -19.713 -6.636 -21.317 1.00 1.00HATOM 3743 HN ALA A1211 -18.834 -3.990 -18.531 1.00 1.00HATOM 3744 N LYS A1212 -22.253 -3.854 -19.666 1.00 1.00NATOM 3745 CA LYS A1212 -23.693 -3.848 -19.504 1.00 1.00CATOM 3746 C LYS A1212 -24.475 -4.295 -20.710 1.00 1.00CATOM 3747 O LYS A1212 -23.948 -4.321 -21.778 1.00 1.00OATOM 3748 CB LYS A1212 -24.099 -2.401 -18.997 1.00 1.00CATOM 3749 CG LYS A1212 -25.590 -2.293 -18.556 1.00 1.00CATOM 3750 CD LYS A1212 -25.799 -0.919 -17.875 1.00 1.00CATOM 3751 CE LYS A1212 -27.250 -0.739 -17.362 1.00 1.00CATOM 3752 NZ LYS A1212 -27.495 0.481 -16.549 1.00 1.00NATOM 3753 HA LYS A1212 -24.016 -4.490 -18.662 1.00 1.00HATOM 3754 HB1 LYS A1212 -23.844 -1.686 -19.808 1.00 1.00HATOM 3755 HB2 LYS A1212 -23.509 -2.195 -18.148 1.00 1.00HATOM 3756 HG1 LYS A1212 -25.837 -3.132 -17.908 1.00 1.00HATOM 3757 HG2 LYS A1212 -26.164 -2.389 -19.491 1.00 1.00HATOM 3758 HD1 LYS A1212 -25.572 -0.160 -18.607 1.00 1.00HATOM 3759 HD2 LYS A1212 -25.082 -0.865 -17.024 1.00 1.00HATOM 3760 HE1 LYS A1212 -28.032 -0.812 -18.143 1.00 1.00HATOM 3761 HE2 LYS A1212 -27.372 -1.571 -16.654 1.00 1.00HATOM 3762 HZ1 LYS A1212 -27.653 1.379 -17.161 1.00 1.00HATOM 3763 HZ2 LYS A1212 -28.325 0.486 -15.918 1.00 1.00HATOM 3764 HZ3 LYS A1212 -26.701 0.653 -15.839 1.00 1.00HATOM 3765 HN LYS A1212 -21.738 -3.170 -19.235 1.00 1.00HATOM 3766 N SER A1213 -25.760 -4.646 -20.542 1.00 1.00NATOM 3767 CA SER A1213 -26.758 -4.542 -21.599 1.00 1.00CATOM 3768 C SER A1213 -28.117 -5.132 -21.207 1.00 1.00CATOM 3769 O SER A1213 -29.132 -4.471 -21.330 1.00 1.00OATOM 3770 CB SER A1213 -26.285 -5.090 -22.979 1.00 1.00CATOM 3771 OG SER A1213 -25.685 -6.412 -22.983 1.00 1.00OATOM 3772 HA SER A1213 -26.992 -3.457 -21.743 1.00 1.00HATOM 3773 HB1 SER A1213 -25.638 4.414 -23.503 1.00 1.00HATOM 3774 HB2 SER A1213 -27.190 -5.213 -23.614 1.00 1.00HATOM 3775 HG SER A1213 -26.282 -7.094 -22.733 1.00 1.00HATOM 3776 HN SER A1213 -26.039 -4.762 -19.598 1.00 1.00HATOM 3777 N VAL A1214 -28.138 -6.422 -20.693 1.00 1.00NATOM 3778 CA VAL A1214 -29.348 -7.114 -20.236 1.00 1.00CATOM 3779 C VAL A1214 -29.099 -7.666 -18.837 1.00 1.00CATOM 3780 O VAL A1214 -29.582 -8.767 -18.502 1.00 1.00OATOM 3781 CB VAL A1214 -29.977 -8.078 -21.286 1.00 1.00CATOM 3782 CG1 VAL A1214 -30.404 -7.295 -22.561 1.00 1.00CATOM 3783 CG2 VAL A1214 -29.089 -9.323 -21.686 1.00 1.00CATOM 3784 HA VAL A1214 -30.029 -6.265 -20.078 1.00 1.00H
ATOM 3785 HB VAL A1214 -30.958 -8.361 -20.870 1.00 1.00HATOM 3786 HG11 VAL A1214 -31.015 -6.361 -22.344 1.00 1.00HATOM 3787 HG12 VAL A1214 -30.968 -7.871 -23.263 1.00 1.00HATOM 3788 HG13 VAL A1214 -29.534 -7.056 -23.133 1.00 1.00HATOM 3789 HG21 VAL A1214 -29.061 -9.958 -20.740 1.00 1.00HATOM 3790 HG22 VAL A1214 -29.650 -9.892 -22.471 1.00 1.00HATOM 3791 HG23 VAL A1214 -28.086 -9.095 -22.002 1.00 1.00HATOM 3792 HN VAL A1214 -27.302 -6.978 -20.631 1.00 1.00HATOM 3793 NGLN A1215 -28.334 -6.932 -18.006 1.00 1.00NATOM 3794 CA GLN A1215 -28.095 -7.350 -16.605 1.00 1.00CATOM 3795 CGLN A1215 -27.475 -8.673 -16.479 1.00 1.00CATOM 3796 OGLN A1215 -27.659 -9.484 -15.553 1.00 1.00OATOM 3797 CB GLN A1215 -29.330 -7.103 -15.751 1.00 1.00CATOM 3798 CG GLN A1215 -30.040 -5.767 -16.129 1.00 1.00CATOM 3799 CD GLN A1215 -29.052 -4.597 -15.892 1.00 1.00CATOM 3800 OE1 GLN A1215 -28.748 -3.951 -16.885 1.00 1.00OATOM 3801 NE2 GLN A1215 -28.533 -4.325 -14.682 1.00 1.00NATOM 3802 HA GLN A1215 -27.396 -6.606 -16.194 1.00 1.00HATOM 3803 HB1 GLN A1215 -30.009 -7.942 -15.880 1.00 1.00HATOM 3804 HB2 GLN A1215 -28.981 -7.198 -14.723 1.00 1.00HATOM 3805 HG1 GLN A1215 -30.356 -5.876 -17.149 1.00 1.00HATOM 3806 HG2 GLN A1215 -30.931 -5.621 -15.551 1.00 1.00HATOM 3807 HE22 GLN A1215 -27.880 -3.532 -14.502 1.00 1.00HATOM 3808 HE21 GLN A1215 -28.685 -4.887 -13.896 1.00 1.00HATOM 3809 HN GLN A1215 -28.033 -6.014 -18.250 1.00 1.00HATOM 3810 NHIS A1216 -26.588 -8.995 -17.481 1.00 1.00NATOM 3811 CA HIS A1216 -25.737 -10.201 -17.388 1.00 1.00CATOM 3812 CHIS A1216 -24.581 -9.832 -16.510 1.00 1.00CATOM 3813 OHIS A1216 -23.486 -9.902 -16.989 1.00 1.00OATOM 3814 CB HIS A1216 -25.329 -10.656 -18.763 1.00 1.00CATOM 3815 CG HIS A1216 -24.448 -9.722 -19.575 1.00 1.00CATOM 3816 ND1 HIS A1216 -23.173 -9.551 -19.425 1.00 1.00NATOM 3817 CD2 HIS A1216 -24.818 -9.026 -20.647 1.00 1.00CATOM 3818 CE1 HIS A1216 -22.687 -8.768 -20.366 1.00 1.00CATOM 3819 NE2 HIS A1216 -23.630 -8.405 -21.093 1.00 1.00NATOM 3820 HA HIS A1216 -26.290 -10.946 -16.881 1.00 1.00HATOM 3821 HB1 HIS A1216 -24.812 -11.587 -18.725 1.00 1.00HATOM 3822 HIB2 HIS A1216 -26.230 -10.778 -19.373 1.00 1.00HATOM 3823 HD2 HIS A1216 -25.848 -9.063 -21.040 1.00 1.00HATOM 3824 HE1 HIS A1216 -21.626 -8.484 -20.515 1.00 1.00HATOM 3825 HD1 HIS A1216 -22.592 -10.002 -18.689 1.00 1.00HATOM 3826 HN HIS A1216 -26.475 -8.428 -18.268 1.00 1.00HATOM 3827 NLEU A1217 -24.787 -9.449 -15.198 1.00 1.00NATOM 3828 CA LEU A1217 -23.637 -9.198 -14.266 1.00 1.00CATOM 3829 CLEU A1217 -23.354 -10.363 -13.307 1.00 1.00CATOM 3830 OLEU A1217 -22.953 -10.115 -12.162 1.00 1.00OATOM 3831 CB LEU A1217 -23.924 -7.958 -13.403 1.00 1.00CATOM 3832 CG LEU A1217 -24.353 -6.615 -14.107 1.00 1.00CATOM 3833 CD1 LEU A1217 -24.753 -5.609 -13.046 1.00 1.00CATOM 3834 CD2 LEU A1217 -23.200 -5.970 -14.947 1.00 1.00CATOM 3835 HA LEU A1217 -22.666 -8.943 -14.723 1.00 1.00HATOM 3836 HB1 LEU A1217 -24.770 -8.242 -12.782 1.00 1.00H
ATOM 3837 HB2 LEU A1217 -23.114 -7.761 -12.720 1.00 1.00HATOM 3838 HG LEU A1217 -25.213 -6.801 -14.735 1.00 1.00HATOM 3839 HD21 LEU A1217 -23.366 -5.005 -15.369 1.00 1.00HATOM 3840 HD22 LEU A1217 -22.318 -5.934 -14.303 1.00 1.00HATOM 3841 HD23 LEU A1217 -22.848 -6.625 -15.769 1.00 1.00HATOM 3842 HD11 LEU A1217 -25.544 -6.060 -12.383 1.00 1.00HATOM 3843 HD12 LEU A1217 -25.233 -4.807 -13.542 1.00 1.00HATOM 3844 HD13 LEU A1217 -23.872 -5.241 -12.481 1.00 1.00HATOM 3845 HN LEU A1217 -25.693 -9.497 -14.786 1.00 1.00HATOM 3846 NGLU A1218 -23.489 -11.657 -13.712 1.00 1.00NATOM 3847 CA GLU A1218 -23.146 -12.732 -12.813 1.00 1.00CATOM 3848 CGLU A1218 -22.028 -13.555 -13.354 1.00 1.00CATOM 3849 OGLU A1218 -20.952 -13.535 -12.780 1.00 1.00OATOM 3850 CB GLU A1218 -24.499 -13.489 -12.546 1.00 1.00CATOM 3851 CG GLU A1218 -25.753 -12.609 -12.336 1.00 1.00CATOM 3852 CD GLU A1218 -25.551 -11.591 -11.209 1.00 1.00CATOM 3853 OE1 GLU A1218 -24.994 -11.946 -10.125 1.00 1.00OATOM 3854 OE2 GLU A1218 -25.906 -10.409 -11.334 1.00 1.00OATOM 3855 HA GLU A1218 -22.826 -12.428 -11.809 1.00 1.00HATOM 3856 HB1 GLU A1218 -24.545 -14.139 -11.599 1.00 1.00HATOM 3857 HB2 GLU A1218 -24.725 -14.057 -13.463 1.00 1.00HATOM 3858 HG1 GLU A1218 -25.993 -12.040 -13.224 1.00 1.00HATOM 3859 HG2 GLU A1218 -26.581 -13.255 -12.049 1.00 1.00HATOM 3860 HN GLU A1218 -23.733 -11.868 -14.684 1.00 1.00HATOM 3861 NSER A1219 -22.100 -14.320 -14.483 1.00 1.00NATOM 3862 CA SER A1219 -20.900 -14.972 -14.987 1.00 1.00CATOM 3863 CSER A1219 -19.811 -14.081 -15.539 1.00 1.00CATOM 3864 OSER A1219 -18.609 -14.187 -15.170 1.00 1.00OATOM 3865 CB SER A1219 -21.329 -16.010 -16.035 1.00 1.00CATOM 3866 OG SER A1219 -22.463 -16.737 -15.444 1.00 1.00OATOM 3867 HA SER A1219 -20.481 -15.549 -14.119 1.00 1.00HATOM 3868 HB1 SER A1219 -21.622 -15.509 -16.947 1.00 1.00HATOM 3869 HB2 SER A1219 -20.489 -16.677 -16.342 1.00 1.00HATOM 3870 HG SER A1219 -22.276 -17.238 -14.654 1.00 1.00HATOM 3871 HN SER A1219 -22.982 -14.448 -14.969 1.00 1.00HATOM 3872 NLEU A1220 -20.074 -13.127 -16.512 1.00 1.00NATOM 3873 CA LEU A1220 -18.939 -12.311 -16.939 1.00 1.00CATOM 3874 CLEU A1220 -18.426 -11.491 -15.734 1.00 1.00CATOM 3875 OLEU A1220 -17.266 -11.198 -15.723 1.00 1.00OATOM 3876 CB LEU A1220 -19.398 -11.398 -18.121 1.00 1.00CATOM 3877 CG LEU A1220 -18.351 -10.300 -18.524 1.00 1.00CATOM 3878 CD1 LEU A1220 -18.444 -10.003 -20.054 1.00 1.00CATOM 3879 CD2 LEU A1220 -18.606 -8.970 -17.785 1.00 1.00CATOM 3880 HA LEU A1220 -18.203 -13.035 -17.343 1.00 1.00HATOM 3881 HB1 LEU A1220 -19.700 -12.053 -19.000 1.00 1.00HATOM 3882 HB2 LEU A1220 -20.281 -10.948 -17.770 1.00 1.00HATOM 3883 HG LEU A1220 -17.302 -10.647 -18.423 1.00 1.00HATOM 3884 HD21 LEU A1220 -18.526 -9.100 -16.688 1.00 1.00HATOM 3885 HD22 LEU A1220 -17.894 -8.160 -18.123 1.00 1.00HATOM 3886 HD23 LEU A1220 -19.604 -8.663 -18.073 1.00 1.00HATOM 3887 HD11 LEU A1220 -17.945 -9.047 -20.219 1.00 1.00HATOM 3888 HD12 LEU A1220 -19.479 -9.952 -20.306 1.00 1.00H
ATOM 3889 HD13 LEU A1220 -17.924 -10.744 -20.672 1.00 1.00HATOM 3890 HN LEU A1220 -21.058 -12.965 -16.744 1.00 1.00HATOM 3891 NPHE A1221 -19.270 -11.235 -14.657 1.00 1.00NATOM 3892 CA PHE A1221 -18.778 -10.634 -13.379 1.00 1.00CATOM 3893 CPHE A1221 -17.855 -11.596 -12.738 1.00 1.00CATOM 3894 OPHE A1221 -16.751 -11.192 -12.452 1.00 1.00OATOM 3895 CB PHE A1221 -19.920 -10.146 -12.476 1.00 1.00CATOM 3896 CG PHE A1221 -19.390 -9.634 -11.133 1.00 1.00CATOM 3897 CD1 PHE A1221 -19.222 -8.266 -11.036 1.00 1.00CATOM 3898 CD2 PHE A1221 -19.073 -10.500 -10.085 1.00 1.00CATOM 3899 CE1 PHE A1221 -18.781 -7.722 -9.842 1.00 1.00CATOM 3900 CE2 PHE A1221 -18.608 -9.951 -8.874 1.00 1.00CATOM 3901 CZ PHE A1221 -18.580 -8.560 -8.721 1.00 1.00CATOM 3902 HA PHE A1221 -18.194 -9.713 -13.649 1.00 1.00HATOM 3903 HB1 PHE A1221 -20.483 -9.361 -13.033 1.00 1.00HATOM 3904 HB2 PHE A1221 -20.676 -10.986 -12.402 1.00 1.00HATOM 3905 HD2 PHE A1221 -19.248 -11.561 -10.206 1.00 1.00HATOM 3906 HE2 PHE A1221 -18.348 -10.618 -8.056 1.00 1.00HATOM 3907 HZ PHE A1221 -18.294 -8.123 -7.779 1.00 1.00HATOM 3908 HE1 PHE A1221 -18.535 -6.712 -9.833 1.00 1.00HATOM 3909 HD1 PHE A1221 -19.384 -7.634 -11.910 1.00 1.00HATOM 3910 HN PHE A1221 -20.214 -11.510 -14.690 1.00 1.00HATOM 3911 NTHR A1222 -18.267 -12.857 -12.484 1.00 1.00NATOM 3912 CA THR A1222 -17.281 -13.748 -11.810 1.00 1.00CATOM 3913 CTHR A1222 -16.012 -13.976 -12.640 1.00 1.00CATOM 3914 OTHR A1222 -14.905 -13.925 -12.125 1.00 1.00OATOM 3915 CB THR A1222 -17.847 -15.173 -11.466 1.00 1.00CATOM 3916 OG1 THR A1222 -18.255 -15.763 -12.727 1.00 1.00OATOM 3917 CG2 THR A1222 -18.974 -15.144 -10.383 1.00 1.00CATOM 3918 HA THR A1222 -16.955 -13.243 -10.872 1.00 1.00HATOM 3919 HB THR A1222 -16.969 -15.740 -11.054 1.00 1.00HATOM 3920 HG1 THR A1222 -18.704 -16.578 -12.544 1.00 1.00HATOM 3921 HG23 THR A1222 -19.757 -14.478 -10.788 1.00 1.00HATOM 3922 HG21 THR A1222 -19.309 -16.160 -10.175 1.00 1.00HATOM 3923 HG22 THR A1222 -18.629 -14.760 -9.423 1.00 1.00HATOM 3924 HN THR A1222 -19.183 -13.138 -12.734 1.00 1.00HATOM 3925 NALA A1223 -16.122 -14.273 -13.960 1.00 1.00NATOM 3926 CA ALA A1223 -14.952 -14.330 -14.822 1.00 1.00CATOM 3927 CALA A1223 -14.101 -13.046 -14.815 1.00 1.00CATOM 3928 OALA A1223 -12.916 -13.181 -14.596 1.00 1.00OATOM 3929 CB ALA A1223 -15.294 -14.755 -16.299 1.00 1.00CATOM 3930 HA ALA A1223 -14.314 -15.152 -14.419 1.00 1.00HATOM 3931 HB1 ALA A1223 -14.456 -14.843 -16.962 1.00 1.00HATOM 3932 HB2 ALA A1223 -15.769 -15.760 -16.224 1.00 1.00HATOM 3933 HB3 ALA A1223 -16.017 -14.046 -16.663 1.00 1.00HATOM 3934 HN ALA A1223 -17.062 -14.375 -14.326 1.00 1.00HATOM 3935 NVAL A1224 -14.611 -11.803 -14.951 1.00 1.00NATOM 3936 CA VAL A1224 -13.850 -10.591 -14.707 1.00 1.00CATOM 3937 CVAL A1224 -13.231 -10.392 -13.336 1.00 1.00CATOM 3938 OVAL A1224 -12.035 -10.187 -13.246 1.00 1.00OATOM 3939 CB VAL A1224 -14.717 -9.292 -14.844 1.00 1.00CATOM 3940 CG1 VAL A1224 -14.085 -7.975 -14.193 1.00 1.00C
ATOM 3941 CG2 VAL A1224 -15.010 -9.052 -16.361 1.00 1.00CATOM 3942 HA VAL A1224 -13.043 -10.492 -15.483 1.00 1.00HATOM 3943 HB VAL A1224 -15.631 -9.413 -14.246 1.00 1.00HATOM 3944 HG11 VAL A1224 -13.020 -7.884 -14.572 1.00 1.00HATOM 3945 HG12 VAL A1224 -14.598 -7.047 -14.490 1.00 1.00HATOM 3946 HG13 VAL A1224 -14.088 -8.057 -13.121 1.00 1.00HATOM 3947 HG21 VAL A1224 -15.486 -9.915 -16.872 1.00 1.00HATOM 3948 HG22 VAL A1224 -15.681 -8.183 -16.541 1.00 1.00HATOM 3949 HG23 VAL A1224 -14.088 -8.801 -16.900 1.00 1.00HATOM 3950 HN VAL A1224 -15.609 -11.708 -15.051 1.00 1.00HATOM 3951 NTHR A1225 -14.023 -10.547 -12.271 1.00 1.00NATOM 3952 CA THR A1225 -13.399 -10.380 -10.975 1.00 1.00CATOM 3953 CTHR A1225 -12.441 -11.528 -10.734 1.00 1.00CATOM 3954 OTHR A1225 -11.496 -11.381 -10.016 1.00 1.00OATOM 3955 CB THR A1225 -14.356 -10.275 -9.760 1.00 1.00CATOM 3956 OG1 THR A1225 -15.044 -11.501 -9.799 1.00 1.00OATOM 3957 CG2 THR A1225 -15.310 -9.102 -9.837 1.00 1.00CATOM 3958 HA THR A1225 -12.768 -9.462 -10.914 1.00 1.00HATOM 3959 HB THR A1225 -13.754 -10.293 -8.834 1.00 1.00HATOM 3960 HG1 THR A1225 -15.640 -11.737 -9.093 1.00 1.00HATOM 3961 HG23 THR A1225 -15.982 -8.949 -9.017 1.00 1.00HATOM 3962 HG21 THR A1225 -15.953 -9.185 -10.746 1.00 1.00HATOM 3963 HG22 THR A1225 -14.668 -8.182 -9.900 1.00 1.00HATOM 3964 HN THR A1225 -15.038 -10.731 -12.344 1.00 1.00HATOM 3965 NASN A1226 -12.672 -12.758 -11.202 1.00 1.00NATOM 3966 CA ASN A1226 -11.762 -13.886 -10.988 1.00 1.00CATOM 3967 CASN A1226 -10.427 -13.661 -11.739 1.00 1.00CATOM 3968 OASN A1226 -9.354 -13.909 -11.184 1.00 1.00OATOM 3969 CB ASN A1226 -12.259 -15.227 -11.522 1.00 1.00CATOM 3970 CG ASN A1226 -11.211 -16.351 -11.297 1.00 1.00CATOM 3971 OD1 ASN A1226 -11.372 -17.070 -10.316 1.00 1.00OATOM 3972 ND2 ASN A1226 -10.156 -16.522 -12.127 1.00 1.00NATOM 3973 HA ASN A1226 -11.601 -13.928 -9.870 1.00 1.00HATOM 3974 HB1 ASN A1226 -13.151 -15.559 -10.906 1.00 1.00HATOM 3975 HB2 ASN A1226 -12.605 -15.184 -12.598 1.00 1.00HATOM 3976 HD22 ASN A1226 -9.498 -17.241 -11.874 1.00 1.00HATOM 3977 HD21 ASN A1226 -10.003 -16.038 -12.998 1.00 1.00HATOM 3978 HN ASN A1226 -13.480 -12.910 -11.739 1.00 1.00HATOM 3979 NPHE A1227 -10.547 -13.219 -13.008 1.00 1.00NATOM 3980 CA PHE A1227 -9.334 -12.847 -13.684 1.00 1.00CATOM 3981 CPHE A1227 -8.675 -11.733 -12.940 1.00 1.00CATOM 3982 OPHE A1227 -7.463 -11.769 -12.795 1.00 1.00OATOM 3983 CB PHE A1227 -9.610 -12.371 -15.127 1.00 1.00CATOM 3984 CG PHE A1227 -10.001 -13.479 -16.131 1.00 1.00CATOM 3985 CD1 PHE A1227 -11.167 -13.420 -16.917 1.00 1.00CATOM 3986 CD2 PHE A1227 -9.074 -14.537 -16.313 1.00 1.00CATOM 3987 CE1 PHE A1227 -11.490 -14.422 -17.810 1.00 1.00CATOM 3988 CE2 PHE A1227 -9.387 -15.568 -17.182 1.00 1.00CATOM 3989 CZ PHE A1227 -10.603 -15.486 -17.890 1.00 1.00CATOM 3990 HA PHE A1227 -8.583 -13.688 -13.678 1.00 1.00HATOM 3991 HB1 PHE A1227 -10.341 -11.531 -15.156 1.00 1.00HATOM 3992 HB2 PHE A1227 -8.653 -11.958 -15.518 1.00 1.00H
ATOM 3993 HD2 PHE A1227 -8.177 -14.646 -15.781 1.00 1.00HATOM 3994 HE2 PHE A1227 -8.685 -16.422 -17.343 1.00 1.00HATOM 3995 HZ PHE A1227 -10.864 -16.305 -18.531 1.00 1.00HATOM 3996 HE1 PHE A1227 -12.381 -14.359 -18.412 1.00 1.00HATOM 3997 HD1 PHE A1227 -11.880 -12.572 -16.926 1.00 1.00HATOM 3998 HN PHE A1227 -11.402 -13.068 -13.460 1.00 1.00HATOM 3999 NLEU A1228 -9.397 -10.699 -12.421 1.00 1.00NATOM 4000 CA LEU A1228 -8.685 -9.577 -11.793 1.00 1.00CATOM 4001 CLEU A1228 -8.133 -10.040 -10.463 1.00 1.00CATOM 4002 OLEU A1228 -7.012 -9.649 -10.076 1.00 1.00OATOM 4003 CB LEU A1228 -9.637 -8.376 -11.608 1.00 1.00CATOM 4004 CG LEU A1228 -9.052 -6.975 -11.102 1.00 1.00CATOM 4005 CD1 LEU A1228 -7.923 -6.403 -11.975 1.00 1.00CATOM 4006 CD2 LEU A1228 -10.163 -5.891 -10.948 1.00 1.00CATOM 4007 HA LEU A1228 -7.797 -9.322 -12.363 1.00 1.00HATOM 4008 HB1 LEU A1228 -10.116 -8.163 -12.565 1.00 1.00HATOM 4009 HB2 LEU A1228 -10.411 -8.768 -10.965 1.00 1.00HATOM 4010 HG LEU A1228 -8.561 -7.152 -10.095 1.00 1.00HATOM 4011 HD21 LEU A1228 -9.785 -4.923 -10.615 1.00 1.00HATOM 4012 HD22 LEU A1228 -10.628 -5.798 -11.945 1.00 1.00HATOM 4013 HD23 LEU A1228 -10.868 -6.311 -10.185 1.00 1.00HATOM 4014 HD11 LEU A1228 -8.154 -6.274 -13.077 1.00 1.00HATOM 4015 HD12 LEU A1228 -7.575 -5.403 -11.608 1.00 1.00HATOM 4016 HD13 LEU A1228 -7.060 -7.052 -11.969 1.00 1.00HATOM 4017 HN LEU A1228 -10.389 -10.762 -12.531 1.00 1.00HATOM 4018 NLEU A1229 -8.914 -10.872 -9.740 1.00 1.00NATOM 4019 CA LEU A1229 -8.524 -11.224 -8.359 1.00 1.00CATOM 4020 CLEU A1229 -7.736 -12.516 -8.252 1.00 1.00CATOM 4021 OLEU A1229 -6.652 -12.535 -7.666 1.00 1.00OATOM 4022 CB LEU A1229 -9.837 -11.279 -7.506 1.00 1.00CATOM 4023 CG LEU A1229 -9.625 -11.527 -5.966 1.00 1.00CATOM 4024 CD1 LEU A1229 -10.893 -11.060 -5.203 1.00 1.00CATOM 4025 CD2 LEU A1229 -9.396 -13.052 -5.649 1.00 1.00CATOM 4026 HA LEU A1229 -7.933 -10.419 -7.954 1.00 1.00HATOM 4027 HB1 LEU A1229 -10.271 -10.264 -7.681 1.00 1.00HATOM 4028 HB2 LEU A1229 -10.547 -11.970 -7.907 1.00 1.00HATOM 4029 HG LEU A1229 -8.764 -10.923 -5.633 1.00 1.00HATOM 4030 HD21 LEU A1229 -8.531 -13.525 -6.111 1.00 1.00HATOM 4031 HD22 LEU A1229 -9.379 -13.162 -4.567 1.00 1.00HATOM 4032 HD23 LEU A1229 -10.286 -13.595 -6.018 1.00 1.00HATOM 4033 HD11 LEU A1229 -10.895 -9.991 -5.090 1.00 1.00HATOM 4034 HD12 LEU A1229 -11.857 -11.401 -5.626 1.00 1.00HATOM 4035 HD13 LEU A1229 -10.880 -11.452 -4.169 1.00 1.00HATOM 4036 HN LEU A1229 -9.797 -11.195 -10.111 1.00 1.00HATOM 4037 NSER A1230 -8.252 -13.577 -8.849 1.00 1.00NATOM 4038 CA SER A1230 -7.611 -14.885 -8.674 1.00 1.00CATOM 4039 CSER A1230 -6.632 -15.225 -9.728 1.00 1.00CATOM 4040 OSER A1230 -6.808 -16.235 -10.409 1.00 1.00OATOM 4041 CB SER A1230 -8.699 -15.984 -8.499 1.00 1.00CATOM 4042 OG SER A1230 -8.062 -17.163 -8.003 1.00 1.00OATOM 4043 HA SER A1230 -7.033 -14.890 -7.763 1.00 1.00HATOM 4044 HB1 SER A1230 -9.437 -15.563 -7.782 1.00 1.00H
ATOM 4045 HB2 SER A1230 -9.290 -16.218 -9.389 1.00 1.00HATOM 4046 HG SER A1230 -7.460 -17.562 -8.642 1.00 1.00HATOM 4047 HN SER A1230 -9.059 -13.506 -9.446 1.00 1.00HATOM 4048 NLEU A1231 -5.608 -14.402 -10.001 1.00 1.00NATOM 4049 CA LEU A1231 -4.710 -14.705 -11.134 1.00 1.00CATOM 4050 CLEU A1231 -3.267 -14.380 -10.847 1.00 1.00CATOM 4051 OLEU A1231 -2.483 -15.318 -10.804 1.00 1.00OATOM 4052 CB LEU A1231 -5.240 -13.890 -12.333 1.00 1.00CATOM 4053 CG LEU A1231 -4.460 -13.963 -13.687 1.00 1.00CATOM 4054 CD1 LEU A1231 -4.218 -15.407 -14.180 1.00 1.00CATOM 4055 CD2 LEU A1231 -5.188 -13.086 -14.727 1.00 1.00CATOM 4056 HA LEU A1231 -4.754 -15.767 -11.522 1.00 1.00HATOM 4057 HB1 LEU A1231 -6.276 -14.171 -12.572 1.00 1.00HATOM 4058 HB2 LEU A1231 -5.225 -12.849 -12.073 1.00 1.00HATOM 4059 HG LEU A1231 -3.475 -13.581 -13.477 1.00 1.00HATOM 4060 HD21 LEU A1231 -4.620 -12.993 -15.675 1.00 1.00HATOM 4061 HD22 LEU A1231 -6.184 -13.553 -14.939 1.00 1.00HATOM 4062 HD23 LEU A1231 -5.298 -12.061 -14.302 1.00 1.00HATOM 4063 HD11 LEU A1231 -3.508 -15.980 -13.573 1.00 1.00HATOM 4064 HD12 LEU A1231 -5.167 -15.925 -14.244 1.00 1.00HATOM 4065 HD13 LEU A1231 -3.777 -15.247 -15.194 1.00 1.00HATOM 4066 HN LEU A1231 -5.521 -13.533 -9.482 1.00 1.00HATOM 4067 NGLY A1232 -2.921 -13.109 -10.615 1.00 1.00NATOM 4068 CA GLY A1232 -1.574 -12.805 -10.153 1.00 1.00CATOM 4069 CGLY A1232 -1.550 -11.704 -9.095 1.00 1.00CATOM 4070 OGLY A1232 -0.517 -11.044 -9.036 1.00 1.00OATOM 4071 HA2 GLY A1232 -0.952 -12.494 -11.047 1.00 1.00HATOM 4072 HA1 GLY A1232 -1.076 -13.718 -9.728 1.00 1.00HATOM 4073 HN GLY A1232 -3.495 -12.310 -10.758 1.00 1.00HATOM 4074 NILE A1233 -2.671 -11.564 -8.354 1.00 1.00NATOM 4075 CA ILE A1233 -2.849 -10.365 -7.450 1.00 1.00CATOM 4076 CILE A1233 -3.611 -10.783 -6.194 1.00 1.00CATOM 4077 OILE A1233 -3.108 -10.539 -5.099 1.00 1.00OATOM 4078 CB ILE A1233 -3.501 -9.172 -8.180 1.00 1.00CATOM 4079 CG1 ILE A1233 -3.056 -8.935 -9.642 1.00 1.00CATOM 4080 CG2 ILE A1233 -3.397 -7.803 -7.428 1.00 1.00CATOM 4081 CD1 ILE A1233 -3.777 -7.847 -10.453 1.00 1.00CATOM 4082 HA ILE A1233 -1.881 -10.031 -7.117 1.00 1.00HATOM 4083 HB ILE A1233 -4.556 -9.473 -8.213 1.00 1.00HATOM 4084 HG11 ILE A1233 -3.195 -9.906 -10.095 1.00 1.00HATOM 4085 HG12 ILE A1233 -1.965 -8.878 -9.679 1.00 1.00HATOM 4086 HD11 ILE A1233 -4.867 -7.933 -10.445 1.00 1.00HATOM 4087 HD12 ILE A1233 -3.469 -6.864 -10.129 1.00 1.00HATOM 4088 HD13 ILE A1233 -3.499 -7.889 -11.493 1.00 1.00HATOM 4089 HG21 ILE A1233 -2.354 -7.460 -7.339 1.00 1.00HATOM 4090 HG22 ILE A1233 -4.022 -7.093 -7.911 1.00 1.00HATOM 4091 HG23 ILE A1233 -3.764 -7.901 -6.389 1.00 1.00HATOM 4092 HN ILE A1233 -3.411 -12.245 -8.460 1.00 1.00HATOM 4093 NHIE A1234 -4.822 -11.374 -6.277 1.00 1.00NATOM 4094 CA HIE A1234 -5.637 -11.555 -5.111 1.00 1.00CATOM 4095 CHIE A1234 -5.668 -10.251 -4.287 1.00 1.00CATOM 4096 OHIE A1234 -5.074 -10.230 -3.212 1.00 1.00O
ATOM 4097 CB HIE A1234 -4.959 -12.785 -4.406 1.00 1.00CATOM 4098 CG HIE A1234 -5.411 -12.993 -3.030 1.00 1.00CATOM 4099 ND1 HIE A1234 -5.027 -12.329 -1.826 1.00 1.00NATOM 4100 CD2 HIE A1234 -6.259 -13.932 -2.588 1.00 1.00CATOM 4101 CE1 HIE A1234 -5.537 -12.905 -0.845 1.00 1.00CATOM 4102 NE2 HIE A1234 -6.309 -13.866 -1.303 1.00 1.00NATOM 4103 HA HIE A1234 -6.693 -11.810 -5.350 1.00 1.00HATOM 4104 HB1 HIE A1234 -5.288 -13.644 -5.035 1.00 1.00HATOM 4105 HB2 HIE A1234 -3.865 -12.707 -4.468 1.00 1.00HATOM 4106 HD2 HIE A1234 -6.710 -14.568 -3.301 1.00 1.00HATOM 4107 HE2 HIE A1234 -6.872 -14.508 -0.693 1.00 1.00HATOM 4108 HE1 HIE A1234 -5.402 -12.664 0.179 1.00 1.00HATOM 4109 HN HIE A1234 -5.283 -11.512 -7.184 1.00 1.00HATOM 4110 NLEU A1235 -6.327 -9.183 -4.820 1.00 1.00NATOM 4111 CA LEU A1235 -6.329 -7.899 -4.125 1.00 1.00CATOM 4112 CLEU A1235 -7.276 -7.878 -2.969 1.00 1.00CATOM 4113 OLEU A1235 -7.875 -8.926 -2.720 1.00 1.00OATOM 4114 CB LEU A1235 -6.560 -6.694 -5.027 1.00 1.00CATOM 4115 CG LEU A1235 -8.030 -6.511 -5.512 1.00 1.00CATOM 4116 CD1 LEU A1235 -8.080 -5.183 -6.240 1.00 1.00CATOM 4117 CD2 LEU A1235 -8.669 -7.612 -6.394 1.00 1.00CATOM 4118 HA LEU A1235 -5.300 -7.768 -3.692 1.00 1.00HATOM 4119 HB1 LEU A1235 -6.219 -5.790 -4.540 1.00 1.00HATOM 4120 HB2 LEU A1235 -5.890 -6.922 -5.893 1.00 1.00HATOM 4121 HG LEU A1235 -8.702 -6.435 -4.601 1.00 1.00HATOM 4122 HD21 LEU A1235 -7.979 -7.823 -7.279 1.00 1.00HATOM 4123 HD22 LEU A1235 -8.934 -8.562 -5.915 1.00 1.00HATOM 4124 HD23 LEU A1235 -9.606 -7.257 -6.865 1.00 1.00HATOM 4125 HD11 LEU A1235 -9.121 -4.844 -6.472 1.00 1.00HATOM 4126 HD12 LEU A1235 -7.545 -5.311 -7.160 1.00 1.00HATOM 4127 HD13 LEU A1235 -7.684 -4.369 -5.621 1.00 1.00HATOM 4128 HN LEU A1235 -6.809 -9.330 -5.635 1.00 1.00HATOM 4129 NASN A1236 -7.450 -6.753 -2.288 1.00 1.00NATOM 4130 CA ASN A1236 -8.581 -6.620 -1.370 1.00 1.00CATOM 4131 CASN A1236 -9.536 -5.633 -1.963 1.00 1.00CATOM 4132 OASN A1236 -9.385 -4.439 -1.682 1.00 1.00OATOM 4133 CB ASN A1236 -8.232 -5.9590.008 1.00 1.00CATOM 4134 CG ASN A1236 -7.358 -4.7320.048 1.00 1.00CATOM 4135 OD1 ASN A1236 -7.740 -3.6470.445 1.00 1.00OATOM 4136 ND2 ASN A1236 -6.074 -4.864 -0.298 1.00 1.00NATOM 4137 HA ASN A1236 -9.089 -7.552 -1.084 1.00 1.00HATOM 4138 HB1 ASN A1236 -9.124 -5.6950.584 1.00 1.00HATOM 4139 HB2 ASN A1236 -7.783 -6.7160.632 1.00 1.00HATOM 4140 HD22 ASN A1236 -5.600 -4.003 -0.397 1.00 1.00HATOM 4141 HD21 ASN A1236 -5.607 -5.750 -0.555 1.00 1.00HATOM 4142 HN ASN A1236 -6.871 -5.973 -2.419 1.00 1.00HATOM 4143 NPRO A1237 -10.487 -5.925 -2.875 1.00 1.00NATOM 4144 CA PRO A1237 -11.219 -4.865 -3.496 1.00 1.00CATOM 4145 CPRO A1237 -12.197 -4.245 -2.517 1.00 1.00CATOM 4146 OPRO A1237 -12.703 -5.027 -1.728 1.00 1.00OATOM 4147 CB PRO A1237 -11.892 -5.568 -4.679 1.00 1.00CATOM 4148 CG PRO A1237 -12.140 -6.955 -4.066 1.00 1.00C
ATOM 4149 CD PRO A1237 -10.956 -7.299 -3.091 1.00 1.00CATOM 4150 HA PRO A1237 -10.521 -4.089 -3.845 1.00 1.00HATOM 4151 HD2 PRO A1237 -10.209 -7.909 -3.589 1.00 1.00HATOM 4152 HD1 PRO A1237 -11.367 -7.825 -2.247 1.00 1.00HATOM 4153 HG2 PRO A1237 -12.303 -7.728 -4.813 1.00 1.00HATOM 4154 HG1 PRO A1237 -13.043 -6.834 -3.516 1.00 1.00HATOM 4155 HB1 PRO A1237 -12.815 -5.110 -4.982 1.00 1.00HATOM 4156 HB2 PRO A1237 -11.186 -5.534 -5.491 1.00 1.00HATOM 4157 NASN A1238 -12.552 -2.944 -2.659 1.00 1.00NATOM 4158 CA ASN A1238 -13.742 -2.410 -1.957 1.00 1.00CATOM 4159 CASN A1238 -14.921 -2.371 -2.978 1.00 1.00CATOM 4160 OASN A1238 -14.560 -2.127 -4.103 1.00 1.00OATOM 4161 CB ASN A1238 -13.562 -1.073 -1.161 1.00 1.00CATOM 4162 CG ASN A1238 -12.432 -1.362 -0.176 1.00 1.00CATOM 4163 OD1 ASN A1238 -12.799 -1.584 0.943 1.00 1.00OATOM 4164 ND2 ASN A1238 -11.152 -1.466 -0.574 1.00 1.00NATOM 4165 HA ASN A1238 -14.058 -3.086 -1.142 1.00 1.00HATOM 4166 HB1 ASN A1238 -13.318 -0.228 -1.791 1.00 1.00HATOM 4167 HB2 ASN A1238 -14.463 -0.811 -0.587 1.00 1.00HATOM 4168 HD22 ASN A1238 -10.447 -1.762 0.103 1.00 1.00HATOM 4169 HD21 ASN A1238 -10.906 -1.245 -1.501 1.00 1.00HATOM 4170 HN ASN A1238 -12.107 -2.391 -3.383 1.00 1.00HATOM 4171 NLYS A1239 -16.247 -2.584 -2.682 1.00 1.00NATOM 4172 CA LYS A1239 -17.163 -2.868 -3.772 1.00 1.00CATOM 4173 CLYS A1239 -18.635 -2.853 -3.476 1.00 1.00CATOM 4174 OLYS A1239 -18.991 -2.995 -2.296 1.00 1.00OATOM 4175 CB LYS A1239 -16.806 -4.258 -4.348 1.00 1.00CATOM 4176 CG LYS A1239 -16.673 -5.523 -3.370 1.00 1.00CATOM 4177 CD LYS A1239 -15.569 -5.468 -2.248 1.00 1.00CATOM 4178 CE LYS A1239 -15.228 -6.838 -1.584 1.00 1.00CATOM 4179 NZ LYS A1239 -14.107 -6.804 -0.652 1.00 1.00NATOM 4180 HA LYS A1239 -16.980 -2.051 -4.514 1.00 1.00HATOM 4181 HB1 LYS A1239 -17.515 -4.487 -5.152 1.00 1.00HATOM 4182 HB2 LYS A1239 -15.857 -4.153 -4.905 1.00 1.00HATOM 4183 HG1 LYS A1239 -16.449 -6.391 -3.995 1.00 1.00HATOM 4184 HG2 LYS A1239 -17.625 -5.775 -2.904 1.00 1.00HATOM 4185 HD1 LYS A1239 -14.740 -5.012 -2.754 1.00 1.00HATOM 4186 HD2 LYS A1239 -15.937 -4.759 -1.454 1.00 1.00HATOM 4187 E1 LYS A1239 -16.142 -7.224 -1.134 1.00 1.00HATOM 4188 HE2 LYS A1239 -15.008 -7.473 -2.440 1.00 1.00HATOM 4189 HZ1 LYS A1239 -13.764 -7.746 -0.359 1.00 1.00HATOM 4190 HZ2 LYS A1239 -14.092 -6.226 0.290 1.00 1.00HATOM 4191 HZ3 LYS A1239 -13.210 -6.403 -1.055 1.00 1.00HATOM 4192 HN LYS A1239 -16.575 -2.542 -1.738 1.00 1.00HATOM 4193 NTHR A1240 -19.502 -2.760 -4.544 1.00 1.00NATOM 4194 CA THR A1240 -20.962 -2.921 -4.434 1.00 1.00CATOM 4195 CTHR A1240 -21.466 -3.518 -5.710 1.00 1.00CATOM 4196 OTHR A1240 -20.897 -3.145 -6.716 1.00 1.00OATOM 4197 CB THR A1240 -21.694 -1.556 -4.131 1.00 1.00CATOM 4198 OG1 THR A1240 -20.921 -0.803 -3.183 1.00 1.00OATOM 4199 CG2 THR A1240 -23.054 -1.811 -3.472 1.00 1.00CATOM 4200 HA THR A1240 -21.137 -3.624 -3.640 1.00 1.00H
ATOM 4201 HB THR A1240 -21.789 -0.921 -5.077 1.00 1.00HATOM 4202 HG1 THR A1240 -20.702 -1.250 -2.359 1.00 1.00HATOM 4203 HG23 THR A1240 -23.501 -0.946 -3.009 1.00 1.00HATOM 4204 HG21 THR A1240 -23.775 -2.232 -4.161 1.00 1.00HATOM 4205 HG22 THR A1240 -22.959 -2.511 -2.612 1.00 1.00HATOM 4206 HN THR A1240 -19.124 -2.640 -5.465 1.00 1.00HATOM 4207 NLYS A1241 -22.450 -4.502 -5.645 1.00 1.00NATOM 4208 CA LYS A1241 -22.675 -5.354 -6.833 1.00 1.00CATOM 4209 CLYS A1241 -24.155 -5.567 -7.143 1.00 1.00CATOM 4210 OLYS A1241 -24.677 -6.407 -6.422 1.00 1.00OATOM 4211 CB LYS A1241 -21.907 -6.590 -6.372 1.00 1.00CATOM 4212 CG LYS A1241 -21.544 -7.632 -7.481 1.00 1.00CATOM 4213 CD LYS A1241 -22.838 -8.375 -7.998 1.00 1.00CATOM 4214 CE LYS A1241 -22.532 -9.456 -9.033 1.00 1.00CATOM 4215 NZ LYS A1241 -23.724 -9.964 -9.718 1.00 1.00NATOM 4216 HA LYS A1241 -22.157 -4.965 -7.740 1.00 1.00HATOM 4217 HB1 LYS A1241 -22.349 -7.064 -5.481 1.00 1.00HATOM 4218 HB2 LYS A1241 -20.925 -6.292 -6.052 1.00 1.00HATOM 4219 HG1 LYS A1241 -21.086 -7.129 -8.300 1.00 1.00HATOM 4220 HG2 LYS A1241 -20.841 -8.340 -7.082 1.00 1.00HATOM 4221 HD1 LYS A1241 -23.490 -8.798 -7.202 1.00 1.00HATOM 4222 HD2 LYS A1241 -23.433 -7.649 -8.594 1.00 1.00HATOM 4223 HE1 LYS A1241 -21.835 -8.994 -9.776 1.00 1.00HATOM 4224 HE2 LYS A1241 -22.071 -10.339 -8.609 1.00 1.00HATOM 4225 HZ1 LYS A1241 -24.221 -9.304 -10.401 1.00 1.00HATOM 4226 HZ2 LYS A1241 -23.498 -10.771 -10.453 1.00 1.00HATOM 4227 HZ3 LYS A1241 -24.507 -10.477 -9.197 1.00 1.00HATOM 4228 HN LYS A1241 -22.946 -4.719 -4.759 1.00 1.00HATOM 4229 NARG A1242 -24.781 -4.811 -8.097 1.00 1.00NATOM 4230 CA ARG A1242 -26.219 -5.111 -8.334 1.00 1.00CATOM 4231 CARG A1242 -27.190 -5.242 -7.203 1.00 1.00CATOM 4232 OARG A1242 -28.052 -4.368 -7.139 1.00 1.00OATOM 4233 CB ARG A1242 -26.148 -6.431 -9.171 1.00 1.00CATOM 4234 CG ARG A1242 -27.596 -6.807 -9.648 1.00 1.00CATOM 4235 CD ARG A1242 -27.651 -8.073 -10.541 1.00 1.00CATOM 4236 NE ARG A1242 -28.913 -8.123 -11.401 1.00 1.00NATOM 4237 CZ ARG A1242 -29.148 -9.130 -12.225 1.00 1.00CATOM 4238 NH1 ARG A1242 -28.323 -10.109 -12.472 1.00 1.00NATOM 4239 NH2 ARG A1242 -30.330 -9.078 -12.848 1.00 1.00NATOM 4240 HA ARG A1242 -26.603 -4.383 -9.047 1.00 1.00HATOM 4241 HB1 ARG A1242 -25.812 -7.324 -8.584 1.00 1.00HATOM 4242 HB2 ARG A1242 -25.427 -6.248 -9.947 1.00 1.00HATOM 4243 HG1 ARG A1242 -28.384 -6.993 -8.845 1.00 1.00HATOM 4244 HG2 ARG A1242 -27.900 -6.016 -10.267 1.00 1.00HATOM 4245 HD1 ARG A1242 -26.762 -8.037 -11.176 1.00 1.00HATOM 4246 HD2 ARG A1242 -27.479 -8.985 -9.945 1.00 1.00HATOM 4247 HE ARG A1242 -29.596 -7.365 -11.340 1.00 1.00HATOM 4248 HH12 ARG A1242 -28.566 -10.827 -13.161 1.00 1.00HATOM 4249 HH11 ARG A1242 -27.432 -10.174 -11.969 1.00 1.00HATOM 4250 HH22 ARG A1242 -30.593 -9.809 -13.564 1.00 1.00HATOM 4251 HH21 ARG A1242 -31.013 -8.355 -12.607 1.00 1.00HATOM 4252 HN ARG A1242 -24.367 -4.132 -8.622 1.00 1.00H
ATOM 4253 N TRP A1243 -27.177 -6.290 -6.378 1.00 1.00 NATOM 4254 CA TRP A1243 -28.386 -6.555 -5.592 1.00 1.00 CATOM 4255 C TRP A1243 -28.556 -5.409 -4.649 1.00 1.00 CATOM 4256 O TRP A1243 -27.551 -4.969 -4.121 1.00 1.00 OATOM 4257 CB TRP A1243 -28.297 -7.951 -4.905 1.00 1.00 CATOM 4258 CG TRP A1243 -27.954 -8.978 -5.907 1.00 1.00 CATOM 4259 CD1 TRP A1243 -26.818 -9.698 -5.971 1.00 1.00 CATOM 4260 CD2 TRP A1243 -28.767 -9.443 -7.095 1.00 1.00 CATOM 4261 NE1 TRP A1243 -26.892 -10.545 -6.928 1.00 1.00 NATOM 4262 CE2 TRP A1243 -28.002 -10.419 -7.617 1.00 1.00 CATOM 4263 CE3 TRP A1243 -29.949 -9.056 -7.694 1.00 1.00 CATOM 4264 CZ2 TRP A1243 -28.340 -11.191 -8.704 1.00 1.00 CATOM 4265 CZ3 TRP A1243 -30.327 -9.787 -8.827 1.00 1.00 CATOM 4266 CH2 TRP A1243 -29.568 -10.890 -9.303 1.00 1.00 CATOM 4267 HA TRP A1243 -29.235 -6.508 -6.219 1.00 1.00 HATOM 4268 HB1 TRP A1243 -27.396 -7.882 -4.249 1.00 1.00 HATOM 4269 HB2 TRP A1243 -29.169 -8.158 -4.255 1.00 1.00 HATOM 4270 HE1 TRP A1243 -26.198 -11.272 -7.095 1.00 1.00 HATOM 4271 HD1 TRP A1243 -25.930 -9.600 -5.341 1.00 1.00 HATOM 4272 HZ2 TRP A1243 -27.714 -12.008 -9.043 1.00 1.00 HATOM 4273 HH2 TRP A1243 -29.970 -11.509 -10.097 1.00 1.00 HATOM 4274 HZ3 TRP A1243 -31.204 -9.581 -9.356 1.00 1.00 HATOM 4275 HE3 TRP A1243 -30.545 -8.254 -7.291 1.00 1.00 HATOM 4276 HN TRP A1243 -26.408 -6.874 -6.260 1.00 1.00 HATOM 4277 N GLY A1244 -29.808 -4.876 -4.476 1.00 1.00 NATOM 4278 CA GLY A1244 -29.978 -3.608 -3.779 1.00 1.00 CATOM 4279 C GLY A1244 -29.944 -2.412 -4.717 1.00 1.00 CATOM 4280 O GLY A1244 -30.594 -1.434 -4.354 1.00 1.00 OATOM 4281 HA2 GLY A1244 -29.200 -3.437 -2.975 1.00 1.00 HATOM 4282 HA1 GLY A1244 -30.960 -3.667 -3.268 1.00 1.00 HATOM 4283 HN GLY A1244 -30.615 -5.277 -4.904 1.00 1.00 HATOM 4284 N TYR A1245 -29.193 -2.386 -5.863 1.00 1.00 NATOM 4285 CA TYR A1245 -29.274 -1.212 -6.730 1.00 1.00 CATOM 4286 C TYR A1245 -28.841 0.009 -5.916 1.00 1.00 CATOM 4287 O TYR A1245 -29.394 1.024 -6.202 1.00 1.00 OATOM 4288 CB TYR A1245 -30.636 -1.225 -7.573 1.00 1.00 CATOM 4289 CG TYR A1245 -30.680 -2.567 -8.351 1.00 1.00 CATOM 4290 CD1 TYR A1245 -30.096 -2.590 -9.604 1.00 1.00 CATOM 4291 CD2 TYR A1245 -31.248 -3.693 -7.734 1.00 1.00 CATOM 4292 CE1 TYR A1245 -30.137 -3.759 -10.331 1.00 1.00 CATOM 4293 CE2 TYR A1245 -31.309 -4.875 -8.508 1.00 1.00 CATOM 4294 CZ TYR A1245 -30.755 -4.901 -9.797 1.00 1.00 CATOM 4295 OH TYR A1245 -30.806 -6.088 -10.524 1.00 1.00 OATOM 4296 HA TYR A1245 -28.436 -1.412 -7.394 1.00 1.00 HATOM 4297 HB2 TYR A1245 -31.572 -1.109 -6.910 1.00 1.00 HATOM 4298 HB1 TYR A1245 -30.655 -0.425 -8.306 1.00 1.00 HATOM 4299 HD2 TYR A1245 -31.677 -3.706 -6.753 1.00 1.00 HATOM 4300 HE2 TYR A1245 -31.817 -5.741 -8.186 1.00 1.00 HATOM 4301 HE1 TYR A1245 -29.657 -3.801 -11.325 1.00 1.00 HATOM 4302 HD1 TYR A1245 -29.553 -1.738 -9.975 1.00 1.00 HATOM 4303 HH TYR A1245 -31.567 -6.027 -11.096 1.00 1.00 HATOM 4304 HN TYR A1245 -28.632 -3.158 -6.228 1.00 1.00 H
ATOM 4305 NSER A1246 -27.911 -0.129 -4.938 1.00 1.00 NATOM 4306 CA SER A1246 -27.437 0.959 -4.083 1.00 1.00 CATOM 4307 CSER A1246 -25.950 1.057 -4.346 1.00 1.00 CATOM 4308 OSER A1246 -25.128 0.813 -3.465 1.00 1.00 OATOM 4309 CB SER A1246 -27.670 0.502 -2.614 1.00 1.00 CATOM 4310 OG SER A1246 -26.887 -0.682 -2.295 1.00 1.00 OATOM 4311 HA SER A1246 -27.951 1.952 -4.288 1.00 1.00 HATOM 4312 HB1 SER A1246 -27.425 1.364 -1.959 1.00 1.00 HATOM 4313 HB2 SER A1246 -28.712 0.209 -2.522 1.00 1.00 HATOM 4314 HG SER A1246 -25.976 -0.461 -2.327 1.00 1.00 HATOM 4315 HN SER A1246 -27.528 -1.052 -4.743 1.00 1.00 HATOM 4316 NLEU A1247 -25.584 1.399 -5.608 1.00 1.00 NATOM 4317 CA LEU A1247 -24.202 1.437 -6.027 1.00 1.00 CATOM 4318 CLEU A1247 -23.564 2.809 -5.582 1.00 1.00 CATOM 4319 OLEU A1247 -23.796 3.800 -6.276 1.00 1.00 OATOM 4320 CB LEU A1247 -24.107 1.221 -7.583 1.00 1.00 CATOM 4321 CG LEU A1247 -24.394 -0.264 -8.053 1.00 1.00 CATOM 4322 CD1 LEU A1247 -23.403 -1.201 -7.343 1.00 1.00 CATOM 4323 CD2 LEU A1247 -25.805 -0.775 -7.836 1.00 1.00 CATOM 4324 HA LEU A1247 -23.565 0.734 -5.458 1.00 1.00 HATOM 4325 HB1 LEU A1247 -23.154 1.605 -7.979 1.00 1.00 HATOM 4326 HB2 LEU A1247 -24.920 1.759 -8.031 1.00 1.00 HATOM 4327 HG LEU A1247 -24.123 -0.185 -9.136 1.00 1.00 HATOM 4328 HD21 LEU A1247 -26.431 0.029 -8.257 1.00 1.00 HATOM 4329 HD22 LEU A1247 -26.050 -1.723 -8.325 1.00 1.00 HATOM 4330 HD23 LEU A1247 -26.110 -0.909 6.785 1.00 1.00 HATOM 4331 HD11 LEU A1247 -23.714 -1.322 -6.294 1.00 1.00 HATOM 4332 HD12 LEU A1247 -23.401 -2.198 -7.840 1.00 1.00 HATOM 4333 HD13 LEU A1247 -22.328 -0.770 -7.433 1.00 1.00 HATOM 4334 HN LEU A1247 -26.204 1.725 -6.260 1.00 1.00 HATOM 4335 NHIS A1248 -22.772 2.887 -4.491 1.00 1.00 NATOM 4336 CA HIS A1248 -22.075 4.139 -4.277 1.00 1.00 CATOM 4337 CHIS A1248 -21.156 4.383 -5.495 1.00 1.00 CATOM 4338 OHIS A1248 -20.589 3.384 -5.944 1.00 1.00 OATOM 4339 CB HIS A1248 -21.106 4.200 -3.091 1.00 1.00 CATOM 4340 CG HIS A1248 -20.120 3.061 -3.041 1.00 1.00 CATOM 4341 ND1 HIS A1248 -19.045 3.081 -3.731 1.00 1.00 NATOM 4342 CD2 HIS A1248 -20.156 1.951 -2.315 1.00 1.00 CATOM 4343 CE1 HIS A1248 -18.294 2.075 -3.480 1.00 1.00 CATOM 4344 NE2 HIS A1248 -18.873 1.345 -2.639 1.00 1.00 NATOM 4345 HA HIS A1248 -22.739 5.032 -4.178 1.00 1.00 HATOM 4346 HB1 HIS A1248 -21.765 4.249 -2.155 1.00 1.00 HATOM 4347 HB2 HIS A1248 -20.527 5.131 -3.034 1.00 1.00 HATOM 4348 HD2 HIS A1248 -20.953 1.575 -1.634 1.00 1.00 HATOM 4349 HE1 HIS A1248 -17.315 1.877 -3.944 1.00 1.00 HATOM 4350 HD1 HIS A1248 -18.776 3.809 -4.398 1.00 1.00 HATOM 4351 HN HIS A1248 -22.668 2.082 -3.898 1.00 1.00 HATOM 4352 NPHE A1249 -20.936 5.662 -6.009 1.00 1.00 NATOM 4353 CA PHE A1249 -19.874 5.829 -6.946 1.00 1.00 CATOM 4354 CPHE A1249 -19.692 7.291 -7.267 1.00 1.00 CATOM 4355 OPHE A1249 -20.633 7.912 -7.709 1.00 1.00 OATOM 4356 CB PHE A1249 -20.131 5.138 -8.284 1.00 1.00 C
ATOM 4357 CG PHE A1249 -18.794 4.902 -9.043 1.00 1.00CATOM 4358 CD1 PHE A1249 -17.987 3.792 -8.841 1.00 1.00CATOM 4359 CD2 PHE A1249 -18.355 5.871 -9.935 1.00 1.00CATOM 4360 CE1 PHE A1249 -16.861 3.502 -9.614 1.00 1.00CATOM 4361 CE2 PHE A1249 -17.208 5.611 -10.711 1.00 1.00CATOM 4362 CZ PHE A1249 -16.462 4.442 -10.538 1.00 1.00CATOM 4363 HA PHE A1249 -18.946 5.470 -6.528 1.00 1.00HATOM 4364 HB1 PHE A1249 -20.731 5.863 -8.840 1.00 1.00HATOM 4365 HB2 PHE A1249 -20.724 4.224 -8.227 1.00 1.00HATOM 4366 HD2 PHE A1249 -18.907 6.804 -10.062 1.00 1.00HATOM 4367 HE2 PHE A1249 -16.904 6.251 -11.527 1.00 1.00HATOM 4368 HZ PHE A1249 -15.574 4.264 -11.144 1.00 1.00HATOM 4369 HE1 PHE A1249 -16.311 2.541 -9.516 1.00 1.00HATOM 4370 HD1 PHE A1249 -18.249 3.083 -8.054 1.00 1.00HATOM 4371 HN PHE A1249 -21.488 6.447 -5.732 1.00 1.00HATOM 4372 N MET A1250 -18.503 7.877 -7.118 1.00 1.00NATOM 4373 CA MET A1250 -18.339 9.265 -7.534 1.00 1.00CATOM 4374 C MET A1250 -19.281 10.205 -6.801 1.00 1.00CATOM 4375 O MET A1250 -19.979 11.007 -7.448 1.00 1.00OATOM 4376 CB MET A1250 -18.372 9.462 -9.104 1.00 1.00CATOM 4377 CG MET A1250 -18.009 10.928 -9.503 1.00 1.00CATOM 4378 SD MET A1250 -16.215 11.204 -9.672 1.00 1.00SATOM 4.379 CE MET A1250 -16.184 13.079 -9.677 1.00 1.00CATOM 4380 HA MET A1250 -17.387 9.701 -7.175 1.00 1.00HATOM 4381 HB1 MET A1250 -19.372 9.244 -9.441 1.00 1.00HATOM 4382 HB2 MET A1250 -17.652 8.798 -9.561 1.00 1.00HATOM 4383 HG1 MET A1250 -18.459 11.179 -10.463 1.00 1.00HATOM 4384 HG2 MET A1250 -18.242 11.669 -8.753 1.00 1.00HATOM 4385 HE1 MET A1250 -15.101 13.371 -9.847 1.00 1.00HATOM 4386 HE2 MET A1250 -16.615 13.461 -8.731 1.00 1.00HATOM 4387 HE3 MET A1250 -16.746 13.410 -10.633 1.00 1.00HATOM 4388 HN MET A1250 -17.718 7.409 -6.652 1.00 1.00HATOM 4389 N GLY A1251 -19.396 10.213 -5.447 1.00 1.00NATOM 4390 CA GLY A1251 -20.192 11.219 -4.852 1.00 1.00CATOM 4391 C GLY A1251 -21.659 11.161 -5.153 1.00 1.00CATOM 4392 O GLY A1251 -22.387 12.123 -4.910 1.00 1.00OATOM 4393 HA2 GLY A1251 -19.791 12.140 -5.170 1.00 1.00HATOM 4394 HA1 GLY A1251 -20.009 11.053 -3.764 1.00 1.00HATOM 4395 HN GLY A1251 -18.883 9.501 -4.894 1.00 1.00HATOM 4396 N TYR A1252 -22.149 9.968 -5.534 1.00 1.00NATOM 4397 CA TYR A1252 -23.601 9.801 -5.606 1.00 1.00CATOM 4398 C TYR A1252 -23.933 8.329 -5.680 1.00 1.00CATOM 4399 O TYR A1252 -22.975 7.546 -5.532 1.00 1.00OATOM 4400 CB TYR A1252 -24.090 10.628 -6.849 1.00 1.00CATOM 4401 CG TYR A1252 -23.019 10.957 -7.884 1.00 1.00CATOM 4402 CD1 TYR A1252 -22.577 10.008 -8.809 1.00 1.00CATOM 4403 CD2 TYR A1252 -22.383 12.223 -7.898 1.00 1.00CATOM 4404 CE1 TYR A1252 -21.857 10.482 -9.916 1.00 1.00CATOM 4405 CE2 TYR A1252 -21.465 12.588 -8.918 1.00 1.00CATOM 4406 CZ TYR A1252 -21.312 11.771 -10.047 1.00 1.00CATOM 4407 OH TYR A1252 -20.726 12.256 -11.215 1.00 1.00OATOM 4408 HA TYR A1252 -24.126 10.112 -4.676 1.00 1.00H
ATOM 4409 HB2 TYR A1252 -24.595 11.574 -6.513 1.00 1.00 HATOM 4410 HB1 TYR A1252 -24.770 10.028 -7.472 1.00 1.00 HATOM 4411 HD2 TYR A1252 -22.703 12.952 -7.119 1.00 1.00 HATOM 4412 HE2 TYR A1252 -20.860 13.460 -8.774 1.00 1.00 HATOM 4413 HE1 TYR A1252 -21.692 9.832 -10.733 1.00 1.00 HATOM 4414 HD1 TYR A1252 -22.788 8.921 -8.684 1.00 1.00 HATOM 4415 HH TYR A1252 -20.332 13.125 -11.144 1.00 1.00 HATOM 4416 HN TYR A1252 -21.613 9.168 -5.685 1.00 1.00 HATOM 4417 NVAL A1253 -25.269 8.018 -5.903 1.00 1.00 NATOM 4418 CA VAL A1253 -25.689 6.642 -6.042 1.00 1.00 CATOM 4419 CVAL A1253 -25.936 6.342 -7.505 1.00 1.00 CATOM 4420 OVAL A1253 -26.500 7.171 -8.157 1.00 1.00 OATOM 4421 CB VAL A1253 -27.007 6.334 -5.225 1.00 1.00 CATOM 4422 CG1 VAL A1253 -27.240 4.800 -5.238 1.00 1.00 CATOM 4423 CG2 VAL A1253 -27.030 6.910 -3.789 1.00 1.00 CATOM 4424 HA VAL A1253 -24.928 6.077 -5.621 1.00 1.00 HATOM 4425 HB VAL A1253 -27.882 6.796 -5.723 1.00 1.00 HATOM 4426 HG11 VAL A1253 -27.293 4.405 -6.224 1.00 1.00 HATOM 4427 HG12 VAL A1253 -26.441 4.230 -4.663 1.00 1.00 HATOM 4428 HG13 VAL A1253 -28.196 4.596 -4.708 1.00 1.00 HATOM 4429 HG21 VAL A1253 -26.910 8.007 -3.800 1.00 1.00 HATOM 4430 HG22 VAL A1253 -26.154 6.502 -3.320 1.00 1.00 HATOM 4431 HG23 VAL A1253 -27.964 6.640 -3.267 1.00 1.00 HATOM 4432 HN VAL A1253 -25.979 8.745 -5.936 1.00 1.00 HATOM 4433 NILE A1254 -25.484 5.191 -8.063 1.00 1.00 NATOM 4434 CA ILE A1254 -25.705 4.875 -9.472 1.00 1.00 CATOM 4435 CILE A1254 -26.942 3.962 -9.550 1.00 1.00 CATOM 4436 OILE A1254 -26.880 2.841 -10.051 1.00 1.00 OATOM 4437 CB ILE A1254 -24.438 4.381 -10.164 1.00 1.00 CATOM 4438 CG1 ILE A1254 -23.231 5.303 -9.905 1.00 1.00 CATOM 4439 CG2 ILE A1254 -24.562 3.996 -11.645 1.00 1.00 CATOM 4440 CD1 ILE A1254 -23.284 6.580 -10.725 1.00 1.00 CATOM 4441 HA ILE A1254 -25.969 5.789 -10.015 1.00 1.00 HATOM 4442 HB ILE A1254 -24.182 3.476 -9.604 1.00 1.00 HATOM 4443 HG11 ILE A1254 -23.134 5.689 -8.868 1.00 1.00 HATOM 4444 HG12 ILE A1254 -22.315 4.734 -10.096 1.00 1.00 HATOM 4445 HD11 ILE A1254 -24.172 7.212 -10.418 1.00 1.00 HATOM 4446 HD12 ILE A1254 -22.430 7.263 -10.607 1.00 1.00 HATOM 4447 HD13 ILE A1254 -23.407 6.348 -11.795 1.00 1.00 HATOM 4448 HG21 ILE A1254 -25.049 4.710 -12.331 1.00 1.00 HATOM 4449 HG22 ILE A1254 -23.549 3.763 -12.071 1.00 1.00 HATOM 4450 HG23 ILE A1254 -25.168 3.055 -11.770 1.00 1.00 HATOM 4451 HN ILE A1254 -25.087 4.465 -7.506 1.00 1.00 HATOM 4452 NGLY A1255 -28.092 4.483 -9.062 1.00 1.00 NATOM 4453 CA GLY A1255 -29.325 3.663 -8.957 1.00 1.00 CATOM 4454 CGLY A1255 -30.431 4.538 -8.437 1.00 1.00 CATOM 4455 OGLY A1255 -31.519 4.530 -9.005 1.00 1.00 OATOM 4456 HA2 GLY A1255 -29.190 2.769 -8.303 1.00 1.00 HATOM 4457 HA1 GLY A1255 -29.595 3.325 -9.915 1.00 1.00 HATOM 4458 HN GLY A1255 -28.108 5.433 -8.745 1.00 1.00 HATOM 4459 NCYS A1256 -30.245 5.355 -7.341 1.00 1.00 NATOM 4460 CA CYS A1256 -31.382 6.027 -6.722 1.00 1.00 C
ATOM 4461 CCYS A1256 -31.250 7.538 -6.620 1.00 1.00 CATOM 4462 OCYS A1256 -31.571 8.130 -5.595 1.00 1.00 OATOM 4463 CB CYS A1256 -31.811 5.452 -5.356 1.00 1.00 CATOM 4464 SG CYS A1256 -30.532 5.619 -4.039 1.00 1.00 SATOM 4465 HA CYS A1256 -32.209 5.931 -7.410 1.00 1.00 HATOM 4466 HB1 CYS A1256 -31.890 4.373 -5.556 1.00 1.00 HATOM 4467 HB2 CYS A1256 -32.774 5.819 -4.970 1.00 1.00 HATOM 4468 HG CYS A1256 -30.512 6.621 -4.029 1.00 1.00 HATOM 4469 HN CYS A1256 -29.418 5.391 -6.833 1.00 1.00 HATOM 4470 NTYR A1257 -30.709 8.170 -7.682 1.00 1.00 NATOM 4471 CA TYR A1257 -30.564 9.629 -7.705 1.00 1.00 CATOM 4472 CTYR A1257 -29.543 10.121 -6.723 1.00 1.00 CATOM 4473 OTYR A1257 -28.500 10.598 -7.146 1.00 1.00 OATOM 4474 CB TYR A1257 -31.919 10.342 -7.500 1.00 1.00 CATOM 4475 CG TYR A1257 -31.797 11.864 -7.577 1.00 1.00 CATOM 4476 CD1 TYR A1257 -31.758 12.647 -6.399 1.00 1.00 CATOM 4477 CD2 TYR A1257 -31.745 12.544 -8.790 1.00 1.00 CATOM 4478 CE1 TYR A1257 -31.523 14.046 -6.42.1 1.00 1.00 CATOM 4479 CE2 TYR A1257 -31.625 13.951 -8.818 1.00 1.00 CATOM 4480 CZ TYR A1257 -31.498 14.679 -7.670 1.00 1.00 CATOM 4481 OH TYR A1257 -31.310 16.032 -7.730 1.00 1.00 OATOM 4482 HA TYR A1257 -30.222 9.938 -8.733 1.00 1.00 HATOM 4483 HB2 TYR A1257 -32.573 9.986 -8.268 1.00 1.00 HATOM 4484 HB1 TYR A1257 -32.477 10.194 -6.548 1.00 1.00 HATOM 4485 HD2 TYR A1257 -31.721 12.005 -9.733 1.00 1.00 HATOM 4486 HE2 TYR A1257 -31.601 14.408 -9.765 1.00 1.00 HATOM 4487 HE1 TYR A1257 -31.439 14.609 -5.487 1.00 1.00 HATOM 4488 HD1 TYR A1257 -31.816 12.167 -5.464 1.00 1.00 HATOM 4489 HH TYR A1257 -30.667 16.358 -8.335 1.00 1.00 HATOM 4490 HN TYR A1257 -30.440 7.600 -8.494 1.00 1.00 HATOM 4491 NGLY A1258 -29.761 10.022 -5.414 1.00 1.00 NATOM 4492 CA GLY A1258 -28.692 10.385 -4.448 1.00 1.00 CATOM 4493 CGLY A1258 -28.375 11.873 -4.506 1.00 1.00 CATOM 4494 OGLY A1258 -28.927 12.584 -3.689 1.00 1.00 OATOM 4495 HA2 GLY A1258 -27.792 9.855 -4.748 1.00 1.00 HATOM 4496 HA1 GLY A1258 -28.996 10.030 -3.450 1.00 1.00 HATOM 4497 HN GLY A1258 -30.604 9.688 -4.997 1.00 1.00 HATOM 4498 NSER A1259 -27.499 12.346 -5.411 1.00 1.00 NATOM 4499 CA SER A1259 -27.186 13.765 -5.525 1.00 1.00 CATOM 4500 CSER A1259 -26.784 14.193 -6.919 1.00 1.00 CATOM 4501 OSER A1259 -25.603 14.421 -7.139 1.00 1.00 OATOM 4502 CB SER A1259 -26.135 13.929 -4.449 1.00 1.00 CATOM 4503 0G SER A1259 -25.726 15.265 -4.261 1.00 1.00 OATOM 4504 HA SER A1259 -28.079 14.438 -5.359 1.00 1.00 HATOM 4505 HB1 SER A1259 -26.503 13.602 -3.463 1.00 1.00 HATOM 4506 HB2 SER A1259 -25.234 13.296 -4.655 1.00 1.00 HATOM 4507 HG SER A1259 -24.939 15.400 -3.744 1.00 1.00 HATOM 4508 HN SER A1259 -27.031 11.668 -6.025 1.00 1.00 HATOM 4509 NLEU A1260 -27.670 14.348 -7.920 1.00 1.00 NATOM 4510 CA LEU A1260 -27.251 14.602 -9.326 1.00 1.00 CATOM 4511 CLEU A1260 -28.127 15.660 -9.896 1.00 1.00 CATOM 4512 OLEU A1260 -29.216 15.837 -9.386 1.00 1.00 O
ATOM 4513 CB LEU A1260 -27.453 13.336 -10.159 1.00 1.00 CATOM 4514 CG LEU A1260 -26.534 12.123 -9.8821.00 1.00 CATOM 4515 CD1 LEU A1260 -27.167 10.904 -10.581 1.00 1.00 CATOM 4516 CD2 LEU A1260 -25.110 12.492 -10.348 1.00 1.00 CATOM 4517 HA LEU A1260 -26.212 14.977 -9.3691.00 1.00 HATOM 4518 HB1 LEU A1260 -28.564 13.101 -10.020 1.00 1.00 HATOM 4519 HB2 LEU A1260 -27.309 13.553 -11.214 1.00 1.00 HATOM 4520 HG LEU A1260 -26.540 11.924 -8.8181.00 1.00 HATOM 4521 HD21 LEU A1260 -24.410 11.696 -10.307 1.00 1.00 HATOM 4522 HD22 LEU A1260 -25.069 12.762 -11.373 1.00 1.00 HATOM 4523 HD23 LEU A1260 -24.772 13.333 -9.7561.00 1.00 HATOM 4524 HD11 LEU A1260 -28.170 10.665 -10.168 1.00 1.00 HATOM 4525 HD12 LEU A1260 -26.527 10.065 -10.283 1.00 1.00 HATOM 4526 HD13 LEU A1260 -27.241 11.095 -11.641 1.00 1.00 HATOM 4527 HN LEU A1260 -28.633 14.171 -7.8331.00 1.00 HATOM 4528 NPRO A1261 -27.729 16.463 -10.910 1.00 1.00 NATOM 4529 CA PRO A1261 -26.389 16.398 -11.523 1.00 1.00 CATOM 4530 CPRO A1261 -25.454 17.204 -10.656 1.00 1.00 CATOM 4531 OPRO A1261 -25.834 18.231 -10.072 1.00 1.00 OATOM 4532 CB PRO A1261 -26.611 17.107 -12.864 1.00 1.00 CATOM 4533 CG PRO A1261 -27.849 18.026 -12.657 1.00 1.00 CATOM 4534 CD PRO A1261 -28.726 17.329 -11.559 1.00 1.00 CATOM 4535 HA PRO A1261 -26.055 15.320 -11.752 1.00 1.00 HATOM 4536 HD2 PRO A1261 -29.537 16.707 -12.022 1.00 1.00 HATOM 4537 HD1 PRO A1261 -29.206 18.072 -10.907 1.00 1.00 HATOM 4538 HG2 PRO A1261 -28.450 18.046 -13.575 1.00 1.00 HATOM 4539 HG1 PRO A1261 -27.584 19.051 -12.393 1.00 1.00 HATOM 4540 HB1 PRO A1261 -25.760 17.687 -13.203 1.00 1.00 HATOM 4541 HB2 PRO A1261 -26.854 16.363 -13.671 1.00 1.00 HATOM 4542 NGLN A1262 -24.188 16.742 -10.523 1.00 1.00 NATOM 4543 CA GLN A1262 -23.280 17.386 -9.5571.00 1.00 CATOM 4544 CGLN A1262 -23.026 18.855 -9.7801.00 1.00 CATOM 4545 OGLN A1262 -22.852 19.633 -8.8421.00 1.00 OATOM 4546 CB GLN A1262 -21.890 16.651 -9.3821.00 1.00 CATOM 4547 CG GLN A1262 -21.004 16.730 -10.669 1.00 1.00 CATOM 4548 CD GLN A1262 -19.784 15.823 -10.614 1.00 1.00 CATOM 4549 OE1 GLN A1262 -19.827 14.828 -11.314 1.00 1.00 OATOM 4550 NE2 GLN A1262 -18.763 16.037 -9.7491.00 1.00 NATOM 4551 HA GLN A1262 -23.791 17.276 -8.5891.00 1.00 HATOM 4552 HB1 GLN A1262 -21.373 17.172 -8.5261.00 1.00 HATOM 4553 HB2 GLN A1262 -22.153 15.577 -9.1441.00 1.00 HATOM 4554 HG1 GLN A1262 -21.587 16.531 -11.641 1.00 1.00 HATOM 4555 HG2 GLN A1262 -20.612 17.761 -10.724 1.00 1.00 HATOM 4556 HE22 GLN A1262 -17.960 15.420 -9.7061.00 1.00 HATOM 4557 HE21 GLN A1262 -18.885 16.778 -9.0431.00 1.00 HATOM 4558 HN GLN A1262 -23.904 15.893 -10.973 1.00 1.00 HATOM 4559 NASP A1263 -23.099 19.292 -11.079 1.00 1.00 NATOM 4560 CA ASP A1263 -22.915 20.739 -11.346 1.00 1.00 CATOM 4561 CASP A1263 -23.983 21.438 -10.492 1.00 1.00 CATOM 4562 OASP A1263 -23.726 22.359 -9.7201.00 1.00 OATOM 4563 CB ASP A1263 -23.033 21.137 -12.797 1.00 1.00 CATOM 4564 CG ASP A1263 -22.690 22.569 -12.921 1.00 1.00 C
ATOM 4565 OD1 ASP A1263 -23.240 23.312 -13.738 1.00 1.00OATOM 4566 OD2 ASP A1263 -21.842 23.056 -12.148 1.00 1.00OATOM 4567 HA ASP A1263 -21.915 21.048 -11.048 1.00 1.00HATOM 4568 HB1 ASP A1263 -22.359 20.439 -13.333 1.00 1.00HATOM 4569 HB2 ASP A1263 -24.061 20.949 -13.100 1.00 1.00HATOM 4570 HN ASP A1263 -23.278 18.674 -11.837 1.00 1.00HATOM 4571 NHIS A1264 -25.253 21.014 -10.578 1.00 1.00NATOM 4572 CA HIS A1264 -26.330 21.704 -9.848 1.00 1.00CATOM 4573 CHIS A1264 -26.414 21.361 -8.355 1.00 1.00CATOM 4574 OHIS A1264 -26.275 22.238 -7.541 1.00 1.00OATOM 4575 CB HIS A1264 -27.701 21.563 -10.568 1.00 1.00CATOM 4576 CG HIS A1264 -27.785 21.939 -12.052 1.00 1.00CATOM 4577 ND1 HIS A1264 -28.864 21.843 -12.795 1.00 1.00NATOM 4578 CD2 HIS A1264 -26.768 22.481 -12.744 1.00 1.00CATOM 4579 CE1 HIS A1264 -28.615 22.288 -13.967 1.00 1.00CATOM 4580 NE2 HIS A1264 -27.424 22.647 -14.014 1.00 1.00NATOM 4581 HA HIS A1264 -26.226 22.792 -10.009 1.00 1.00HATOM 4582 HB1 HIS A1264 -28.105 20.567 -10.516 1.00 1.00HATOM 4583 HB2 HIS A1264 -28.460 22.183 -10.057 1.00 1.00HATOM 4584 HD2 HIS A1264 -25.789 22.754 -12.534 1.00 1.00HATOM 4585 HE1 HIS A1264 -29.180 22.471 -14.844 1.00 1.00HATOM 4586 HD1 HIS A1264 -29.741 21.436 -12.473 1.00 1.00HATOM 4587 HN HIS A1264 -25.485 20.235 -11.157 1.00 1.00HATOM 4588 NILE A1265 -26.756 20.088 -8.011 1.00 1.00NATOM 4589 CA ILE A1265 -27.074 19.753 -6.596 1.00 1.00CATOM 4590 CILE A1265 -25.791 19.433 -5.755 1.00 1.00CATOM 4591 OILE A1265 -25.956 18.986 -4.623 1.00 1.00OATOM 4592 CB ILE A1265 -28.145 18.576 -6.535 1.00 1.00CATOM 4593 CG1 ILE A1265 -28.878 18.641 -5.160 1.00 1.00CATOM 4594 CG2 ILE A1265 -27.527 17.186 -6.849 1.00 1.00CATOM 4595 CD1 ILE A1265 -29.984 17.571 -5.136 1.00 1.00CATOM 4596 HA ILE A1265 -27.555 20.668 -6.132 1.00 1.00HATOM 4597 HB ILE A1265 -28.842 18.816 -7.332 1.00 1.00HATOM 4598 HG11 ILE A1265 -28.222 18.343 -4.283 1.00 1.00HATOM 4599 HG12 ILE A1265 -29.285 19.621 -4.927 1.00 1.00HATOM 4600 HD11 ILE A1265 -30.563 17.540 -4.183 1.00 1.00HATOM 4601 HD12 ILE A1265 -30.678 17.779 -5.947 1.00 1.00HATOM 4602 HD13 ILE A1265 -29.572 16.577 -5.395 1.00 1.00HATOM 4603 HG21 ILE A1265 -27.151 16.741 -5.952 1.00 1.00HATOM 4604 HG22 ILE A1265 -28.329 16.640 -7.355 1.00 1.00HATOM 4605 HG23 ILE A1265 -26.716 17.395 -7.579 1.00 1.00HATOM 4606 HN ILE A1265 -26.753 19.377 -8.699 1.00 1.00HATOM 4607 NILE A1266 -24.576 19.767 -6.300 1.00 1.00NATOM 4608 CA ILE A1266 -23.394 19.877 -5.494 1.00 1.00CATOM 4609 CILE A1266 -22.687 21.188 -5.757 1.00 1.00CATOM 4610 OILE A1266 -22.428 21.904 -4.809 1.00 1.00OATOM 4611 CB ILE A1266 -22.313 18.730 -5.593 1.00 1.00CATOM 4612 CG1 ILE A1266 -23.000 17.416 -5.240 1.00 1.00CATOM 4613 CG2 ILE A1266 -21.076 19.059 -4.673 1.00 1.00CATOM 4614 CD1 ILE A1266 -22.118 16.139 -5.224 1.00 1.00CATOM 4615 HA ILE A1266 -23.680 19.931 -4.466 1.00 1.00HATOM 4616 HB ILE A1266 -21.833 18.720 -6.591 1.00 1.00H
ATOM 4617 HG11 ILE A1266 -23.452 17.489 -4.219 1.00 1.00 HATOM 4618 HG12 ILE A1266 -23.837 17.199 -5.904 1.00 1.00 HATOM 4619 HD11 ILE A1266 -21.575 16.062 -6.151 1.00 1.00 HATOM 4620 HD12 ILE A1266 -21.409 16.196 -4.393 1.00 1.00 HATOM 4621 HD13 ILE A1266 -22.824 15.284 -5.074 1.00 1.00 HATOM 4622 HG21 ILE A1266 -20.327 18.235 -4.775 1.00 1.00 HATOM 4623 HG22 ILE A1266 -20.522 19.980 -4.891 1.00 1.00 HATOM 4624 HG23 ILE A1266 -21.490 19.157 -3.669 1.00 1.00 HATOM 4625 HN ILE A1266 -24.454 20.019 -7.282 1.00 1.00 HATOM 4626 NGLN A1267 -22.348 21.576 -7.045 1.00 1.00 NATOM 4627 CA GLN A1267 -21.567 22.786 -7.244 1.00 1.00 CATOM 4628 CGLN A1267 -22.368 24.018 -7.125 1.00 1.00 CATOM 4629 OGLN A1267 -21.944 24.996 -6.479 1.00 1.00 OATOM 4630 CB GLN A1267 -20.708 22.772 -8.553 1.00 1.00 CATOM 4631 CG GLN A1267 -19.626 21.634 -8.437 1.00 1.00 CATOM 4632 CD GLN A1267 -18.789 21.975 -7.231 1.00 1.00 CATOM 4633 OE1 GLN A1267 -18.459 23.122 -7.041 1.00 1.00 OATOM 4634 NE2 GLN A1267 -18.464 21.005 -6.337 1.00 1.00 NATOM 4635 HA GLN A1267 -20.919 22.842 -6.410 1.00 1.00 HATOM 4636 HB1 GLN A1267 -21.265 22.528 -9.441 1.00 1.00 HATOM 4637 HB2 GLN A1267 -20.177 23.704 -8.782 1.00 1.00 HATOM 4638 HG1 GLN A1267 -20.115 20.664 -8.294 1.00 1.00 HATOM 4639 HG2 GLN A1267 -19.032 21.526 -9.379 1.00 1.00 HATOM 4640 HE22 GLN A1267 -17.946 21.314 -5.553 1.00 1.00 HATOM 4641 HE21 GLN A1267 -18.690 20.022 -6.416 1.00 1.00 HATOM 4642 HN GLN A1267 -22.537 21.007 -7.827 1.00 1.00 HATOM 4643 NLYS A1268 -23.614 24.109 -7.736 1.00 1.00 NATOM 4644 CA LYS A1268 -24.357 25.351 -7.569 1.00 1.00 CATOM 4645 CLYS A1268 -24.857 25.458 -6.151 1.00 1.00 CATOM 4646 OLYS A1268 -24.789 26.481 -5.511 1.00 1.00 OATOM 4647 CB LYS A1268 -25.425 25.527 -8.724 1.00 1.00 CATOM 4648 CG LYS A1268 -24.847 26.163 -10.048 1.00 1.00 CATOM 4649 CD LYS A1268 -23.759 25.354 -10.762 1.00 1.00 CATOM 4650 CE LYS A1268 -23.152 26.182 -11.950 1.00 1.00 CATOM 4651 NZ LYS A1268 -22.147 25.335 -12.718 1.00 1.00 NATOM 4652 HA LYS A1268 -23.745 26.170 -7.689 1.00 1.00 HATOM 4653 HB1 LYS A1268 -25.957 24.564 -8.808 1.00 1.00 HATOM 4654 HB2 LYS A1268 -26.193 26.274 -8.333 1.00 1.00 HATOM 4655 HG1 LYS A1268 -25.689 26.211 -10.742 1.00 1.00 HATOM 4656 HG2 LYS A1268 -24.533 27.183 -9.906 1.00 1.00 HATOM 4657 HD1 LYS A1268 -23.018 25.071 -10.011 1.00 1.00 HATOM 4658 HD2 LYS A1268 -24.142 24.415 -11.186 1.00 1.00 HATOM 4659 HE1 LYS A1268 -23.990 26.514 -12.597 1.00 1.00 HATOM 4660 HE2 LYS A1268 -22.684 27.098 -11.586 1.00 1.00 HATOM 4661 HZ1 LYS A1268 -21.538 24.673 -12.118 1.00 1.00 HATOM 4662 HZ2 LYS A1268 -22.571 24.768 -13.502 1.00 1.00 HATOM 4663 HZ3 LYS A1268 -21.373 26.022 -13.128 1.00 1.00 HATOM 4664 HN LYS A1268 -23.953 23.326 -8.303 1.00 1.00 HATOM 4665 NILE A1269 -25.405 24.379 -5.510 1.00 1.00 NATOM 4666 CA ILE A1269 -25.536 24.397 -4.075 1.00 1.00 CATOM 4667 CILE A1269 -24.207 24.774 -3.362 1.00 1.00 CATOM 4668 OILE A1269 -24.263 25.511 -2.388 1.00 1.00 O
ATOM 4669 CB ILE A1269 -26.398 23.233 -3.442 1.00 1.00CATOM 4670 CG1 ILE A1269 -25.644 21.926 -3.454 1.00 1.00CATOM 4671 CG2 ILE A1269 -27.807 23.040 -3.988 1.00 1.00CATOM 4672 CD1 ILE A1269 -26.489 20.824 -2.726 1.00 1.00CATOM 4673 HA ILE A1269 -26.219 25.238 -3.847 1.00 1.00HATOM 4674 HB ILE A1269 -26.524 23.472 -2.357 1.00 1.00HATOM 4675 HG11 ILE A1269 -25.476 21.677 -4.494 1.00 1.00HATOM 4676 HG12 ILE A1269 -24.670 22.106 -2.995 1.00 1.00HATOM 4677 HD11 ILE A1269 -27.290 20.427 -3.327 1.00 1.00HATOM 4678 HD12 ILE A1269 -25.856 20.001 -2.525 1.00 1.00HATOM 4679 HD13 ILE A1269 -26.893 21.125 -1.724 1.00 1.00HATOM 4680 HG21 ILE A1269 -27.645 22.850 -5.051 1.00 1.00HATOM 4681 HG22 ILE A1269 -28.453 22.275 -3.523 1.00 1.00HATOM 4682 HG23 ILE A1269 -28.310 23.987 -3.895 1.00 1.00HATOM 4683 HN ILE A1269 -25.572 23.569 -6.085 1.00 1.00HATOM 4684 NLYS A1270 -22.998 24.367 -3.808 1.00 1.00NATOM 4685 CA LYS A1270 -21.745 24.846 -3.219 1.00 1.00CATOM 4686 CLYS A1270 -21.699 26.323 -3.332 1.00 1.00CATOM 4687 OLYS A1270 -21.368 27.008 -2.367 1.00 1.00OATOM 4688 CB LYS A1270 -20.488 24.170 -3.815 1.00 1.00CATOM 4689 CG LYS A1270 -19.062 24.642 -3.403 1.00 1.00CATOM 4690 CD LYS A1270 -18.692 26.089 -3.852 1.00 1.00CATOM 4691 CE LYS A1270 -18.816 26.359 -5.398 1.00 1.00CATOM 4692 NZ LYS A1270 -17.843 25.701 -6.342 1.00 1.00NATOM 4693 HA LYS A1270 -21.706 24.621 -2.133 1.00 1.00HATOM 4694 HB1 LYS A1270 -20.529 23.122 -3.480 1.00 1.00HATOM 4695 HB2 LYS A1270 -20.388 24.144 -4.864 1.00 1.00HATOM 4696 HG1 LYS A1270 -18.876 24.479 -2.314 1.00 1.00HATOM 4697 HG2 LYS A1270 -18.323 24.018 -3.912 1.00 1.00HATOM 4698 HD1 LYS A1270 -19.276 26.822 -3.296 1.00 1.00HATOM 4699 HD2 LYS A1270 -17.622 26.268 -3.540 1.00 1.00HATOM 4700 HE1 LYS A1270 -19.788 26.149 -5.863 1.00 1.00HATOM 4701 HE2 LYS A1270 -18.721 27.447 -5.542 1.00 1.00HATOM 4702 HZ1 LYS A1270 -17.731 26.159 -7.315 1.00 1.00HATOM 4703 HZ2 LYS A1270 -16.873 25.946 -6.065 1.00 1.00HATOM 4704 HZ3 LYS A1270 -17.841 24.633 -6.358 1.00 1.00HATOM 4705 HN LYS A1270 -22.915 23.714 -4.596 1.00 1.00HATOM 4706 NGLU A1271 -22.134 26.979 -4.458 1.00 1.00NATOM 4707 CA GLU A1271 -22.408 28.402 -4.462 1.00 1.00CATOM 4708 CGLU A1271 -23.162 28.805 -3.230 1.00 1.00CATOM 4709 OGLU A1271 -22.599 29.692 -2.598 1.00 1.00OATOM 4710 CB GLU A1271 -22.928 29.016 -5.806 1.00 1.00CATOM 4711 CG GLU A1271 -24.374 29.519 -5.829 1.00 1.00CATOM 4712 CD GLU A1271 -24.500 30.969 -5.382 1.00 1.00CATOM 4713 OE1 GLU A1271 -23.748 31.432 -4.489 1.00 1.00OATOM 4714 OE2 GLU A1271 -25.377 31.706 -5.866 1.00 1.00OATOM 4715 HA GLU A1271 -21.391 28.822 -4.345 1.00 1.00HATOM 4716 HB1 GLU A1271 -22.931 28.302 -6.614 1.00 1.00HATOM 4717 HB2 GLU A1271 -22.353 29.882 -6.162 1.00 1.00HATOM 4718 HG1 GLU A1271 -24.752 29.499 -6.897 1.00 1.00HATOM 4719 HG2 GLU A1271 -25.039 28.861 -5.281 1.00 1.00HATOM 4720 HN GLU A1271 -22.287 26.431 -5.283 1.00 1.00H
ATOM 4721 NCYS A1272 -24.377 28.177 -2.953 1.00 1.00NATOM 4722 CA CYS A1272 -25.028 28.618 -1.728 1.00 1.00CATOM 4723 CCYS A1272 -24.019 28.778 -0.634 1.00 1.00CATOM 4724 OCYS A1272 -23.905 29.881 -0.068 1.00 1.00OATOM 4725 CB CYS A1272 -26.287 27.868 -1.090 1.00 1.00CATOM 4726 SG CYS A1272 -26.038 26.266 -0.273 1.00 1.00SATOM 4727 HA CYS A1272 -25.479 29.580 -1.983 1.00 1.00HATOM 4728 HB1 CYS A1272 -27.037 27.708 -1.889 1.00 1.00HATOM 4729 HB2 CYS A1272 -26.851 28.515 -0.364 1.00 1.00HATOM 4730 HN CYS A1272 -24.742 27.449 -3.500 1.00 1.00HATOM 4731 NPHE A1273 -23.218 27.701 -0.319 1.00 1.00NATOM 4732 CA PHE A1273 -22.126 27.837 0.652 1.00 1.00CATOM 4733 CPHE A1273 -21.307 29.088 0.340 1.00 1.00CATOM 4734 OPHE A1273 -21.192 29.971 1.188 1.00 1.00OATOM 4735 CB PHE A1273 -21.253 26.564 0.608 1.00 1.00CATOM 4736 CG PHE A1273 -19.840 26.746 1.152 1.00 1.00CATOM 4737 CD1 PHE A1273 -19.619 27.238 2.433 1.00 1.00CATOM 4738 CD2 PHE A1273 -18.685 26.442 0.409 1.00 1.00CATOM 4739 CE1 PHE A1273 -18.356 27.482 2.917 1.00 1.00CATOM 4740 CE2 PHE A1273 -17.392 26.603 0.952 1.00 1.00CATOM 4741 CZ PHE A1273 -17.228 27.227 2.183 1.00 1.00CATOM 4742 HA PHE A1273 -22.454 28.073 1.656 1.00 1.00HATOM 4743 HB1 PHE A1273 -21.021 26.253 -0.433 1.00 1.00HATOM 4744 HB2 PHE A1273 -21.839 25.724 1.065 1.00 1.00HATOM 4745 HD2 PHE A1273 -18.776 26.146 -0.609 1.00 1.00HATOM 4746 HE2 PHE A1273 -16.550 26.261 0.441 1.00 1.00HATOM 4747 HZ PHE A1273 -16.332 27.509 2.645 1.00 1.00HATOM 4748 HE1 PHE A1273 -18.212 27.892 3.911 1.00 1.00HATOM 4749 HD1 PHE A1273 -20.413 27.389 3.153 1.00 1.00HATOM 4750 HN PHE A1273 -23.401 26.877 -0.828 1.00 1.00HATOM 4751 NARG A1274 -20.694 29.098 -0.853 1.00 1.00NATOM 4752 CA ARG A1274 -19.579 30.021 -0.925 1.00 1.00CATOM 4753 CARG A1274 -20.163 31.425 -0.719 1.00 1.00CATOM 4754 OARG A1274 -19.492 32.211 -0.080 1.00 1.00OATOM 4755 CB ARG A1274 -18.682 29.902 -2.184 1.00 1.00CATOM 4756 CG ARG A1274 -17.410 30.836 -2.132 1.00 1.00CATOM 4757 CD ARG A1274 -16.402 30.500 -0.986 1.00 1.00CATOM 4758 NE ARG A1274 -15.137 31.089 -1.376 1.00 1.00NATOM 4759 CZ ARG A1274 -13.912 30.624 -1.146 1.00 1.00CATOM 4760 NH1 ARG A1274 -13.583 29.569 -0.395 1.00 1.00NATOM 4761 NH2 ARG A1274 -12.938 31.256 -1.722 1.00 1.00NATOM 4762 HA ARG A1274 -18.858 29.846 -0.105 1.00 1.00HATOM 4763 HB1 ARG A1274 -19.333 30.210 -2.995 1.00 1.00HATOM 4764 HB2 ARG A1274 -18.353 28.852 -2.354 1.00 1.00HATOM 4765 HG1 ARG A1274 -17.689 31.915 -2.089 1.00 1.00HATOM 4766 HG2 ARG A1274 -16.919 30.664 -3.134 1.00 1.00HATOM 4767 HD1 ARG A1274 -16.351 29.381 -1.000 1.00 1.00HATOM 4768 HD2 ARG A1274 -16.685 30.950 0.001 1.00 1.00HATOM 4769 HE ARG A1274 -15.196 31.983 -1.860 1.00 1.00HATOM 4770 HH12 ARG A1274 -12.634 29.263 -0.260 1.00 1.00HATOM 4771 HH11 ARG A1274 -14.328 28.981 -0.018 1.00 1.00HATOM 4772 HH22 ARG A1274 -12.016 30.905 -1.563 1.00 1.00H
ATOM 4773 HH21 ARG A1274 -13.043 32.123 -2.304 1.00 1.00 HATOM 4774 HN ARG A1274 -20.789 28.397 -1.533 1.00 1.00 HATOM 4775 NLYS A1275 -21.373 31.708 -1.231 1.00 1.00 NATOM 4776 CA LYS A1275 -21.857 33.144 -1.277 1.00 1.00 CATOM 4777 CLYS A1275 -22.813 33.412 -0.131 1.00 1.00 CATOM 4778 OLYS A1275 -23.423 34.485 -0.106 1.00 1.00 OATOM 4779 CB LYS A1275 -22.345 33.517 -2.687 1.00 1.00 CATOM 4780 CG LYS A1275 -22.401 35.015 -3.034 1.00 1.00 CATOM 4781 CD LYS A1275 -23.367 35.262 -4.262 1.00 1.00 CATOM 4782 CE LYS A1275 -22.855 34.715 -5.616 1.00 1.00 CATOM 4783 NZ LYS A1275 -23.375 33.350 -5.857 1.00 1.00 NATOM 4784 HA LYS A1275 -21.030 33.833 -1.205 1.00 1.00 HATOM 4785 HB1 LYS A1275 -23.300 33.033 -2.796 1.00 1.00 HATOM 4786 HB2 LYS A1275 -21.716 33.097 -3.464 1.00 1.00 HATOM 4787 HG1 LYS A1275 -21.440 35.406 -3.271 1.00 1.00 HATOM 4788 HG2 LYS A1275 -22.870 35.619 -2.241 1.00 1.00 HATOM 4789 HD1 LYS A1275 -23.440 36.378 4.380 1.00 1.00 HATOM 4790 HD2 LYS A1275 -24.400 34.928 -4.074 1.00 1.00 HATOM 4791 HE1 LYS A1275 -21.753 34.731 -5.653 1.00 1.00 HATOM 4792 HE2 LYS A1275 -23.224 35.452 -6.394 1.00 1.00 HATOM 4793 HZ1 LYS A1275 -24.403 33.206 -5.742 1.00 1.00 HATOM 4794 HZ2 LYS A1275 -22.887 32.634 -5.250 1.00 1.00 HATOM 4795 HZ3 LYS A1275 -23.085 33.074 -6.889 1.00 1.00 HATOM 4796 HN LYS A1275 -22.017 31.066 -1.644 1.00 1.00 HATOM 4797 NLEU A1276 -23.067 32.472 0.832 1.00 1.00 NATOM 4798 CA LEU A1276 -24.034 32.794 1.881 1.00 1.00 CATOM 4799 CLEU A1276 -23.840 34.182 2.478 1.00 1.00 CATOM 4800 OLEU A1276 -24.836 34.803 2.705 1.00 1.00 OATOM 4801 CB LEU A1276 -24.072 31.704 3.046 1.00 1.00 CATOM 4802 CG LEU A1276 -25.471 31.180 3.431 1.00 1.00 CATOM 4803 CD1 LEU A1276 -26.311 32.295 4.042 1.00 1.00 CATOM 4804 CD2 LEU A1276 -26.275 30.318 2.425 1.00 1.00 CATOM 4805 HA LEU A1276 -25.010 32.685 1.410 1.00 1.00 HATOM 4806 HB1 LEU A1276 -23.521 30.832 2.725 1.00 1.00 HATOM 4807 HB2 LEU A1276 -23.478 32.043 3.905 1.00 1.00 HATOM 4808 HG LEU A1276 -25.269 30.442 4.225 1.00 1.00 HATOM 4809 HD21 LEU A1276 -26.551 30.897 1.548 1.00 1.00 HATOM 4810 HD22 LEU A1276 -25.663 29.476 2.133 1.00 1.00 HATOM 4811 HD23 LEU A1276 -27.191 29.945 2.853 1.00 1.00 HATOM 4812 HD11 LEU A1276 -26.667 32.997 3.275 1.00 1.00 HATOM 4813 HD12 LEU A1276 -27.168 31.843 4.535 1.00 1.00 HATOM 4814 HD13 LEU A1276 -25.722 32.832 4.797 1.00 1.00 HATOM 4815 HN LEU A1276 -22.672 31.534 0.763 1.00 1.00 HATOM 4816 NPRO A1277 -22.620 34.703 2.794 1.00 1.00 NATOM 4817 CA PRO A1277 -22.479 35.984 3.442 1.00 1.00 CATOM 4818 CPRO A1277 -22.884 36.048 4.922 1.00 1.00 CATOM 4819 OPRO A1277 -23.209 37.099 5.413 1.00 1.00 OATOM 4820 CB PRO A1277 -20.923 36.184 3.310 1.00 1.00 CATOM 4821 CG PRO A1277 -20.345 34.757 3.209 1.00 1.00 CATOM 4822 CD PRO A1277 -21.418 33.956 2.494 1.00 1.00 CATOM 4823 HA PRO A1277 -22.953 36.812 2.941 1.00 1.00 HATOM 4824 HD2 PRO A1277 -21.494 32.912 2.770 1.00 1.00 H
ATOM 4825 HD1 PRO A1277 -21.124 34.112 1.465 1.00 1.00HATOM 4826 HG2 PRO A1277 -20.242 34.391 4.261 1.00 1.00HATOM 4827 HG1 PRO A1277 -19.359 34.682 2.736 1.00 1.00HATOM 4828 HB1 PRO A1277 -20.663 36.739 2.400 1.00 1.00HATOM 4829 HB2 PRO A1277 -20.556 36.732 4.196 1.00 1.00HATOM 4830 NVAL A1278 -22.690 34.915 5.699 1.00 1.00NATOM 4831 CA VAL A1278 -23.044 34.901 7.103 1.00 1.00CATOM 4832 CVAL A1278 -24.554 34.810 7.284 1.00 1.00CATOM 4833 OVAL A1278 -25.044 33.788 7.744 1.00 1.00OATOM 4834 CB VAL A1278 -22.242 35.880 7.989 1.00 1.00CATOM 4835 CG1 VAL A1278 -22.677 35.726 9.498 1.00 1.00CATOM 4836 CG2 VAL A1278 -20.730 35.639 7.776 1.00 1.00CATOM 4837 HA VAL A1278 -22.687 33.976 7.450 1.00 1.00HATOM 4838 HB VAL A1278 -22.491 36.871 7.671 1.00 1.00HATOM 4839 HG11 VAL A1278 -22.474 34.687 9.924 1.00 1.00HATOM 4840 HG12 VAL A1278 -22.248 36.541 10.174 1.00 1.00HATOM 4841 HG13 VAL A1278 -23.823 35.700 9.597 1.00 1.00HATOM 4842 HG21 VAL A1278 -20.446 34.672 8.184 1.00 1.00HATOM 4843 HG22 VAL A1278 -20.516 35.658 6.691 1.00 1.00HATOM 4844 HG23 VAL A1278 -20.122 36.459 8.179 1.00 1.00HATOM 4845 HN VAL A1278 -22.438 34.017 5.306 1.00 1.00HATOM 4846 NASN A1279 -25.220 35.925 6.932 1.00 1.00NATOM 4847 CA ASN A1279 -26.686 35.935 6.993 1.00 1.00CATOM 4848 CASN A1279 -27.224 35.800 8.423 1.00 1.00CATOM 4849 OASN A1279 -27.783 36.760 8.868 1.00 1.00OATOM 4850 CB ASN A1279 -27.343 34.900 6.086 1.00 1.00CATOM 4851 CG ASN A1279 -28.812 35.143 6.189 1.00 1.00CATOM 4852 OD1 ASN A1279 -29.348 36.154 5.752 1.00 1.00OATOM 4853 ND2 ASN A1279 -29.582 34.219 6.717 1.00 1.00NATOM 4854 HA ASN A1279 -26.933 36.968 6.736 1.00 1.00HATOM 4855 HB1 ASN A1279 -27.081 35.007 5.001 1.00 1.00HATOM 4856 HB2 ASN A1279 -27.014 33.909 6.372 1.00 1.00HATOM 4857 HD22 ASN A1279 -29.182 33.457 7.260 1.00 1.00HATOM 4858 HD21 ASN A1279 -30.512 34.488 6.813 1.00 1.00HATOM 4859 HN ASN A1279 -24.791 36.746 6.529 1.00 1.00HATOM 4860 NARG A1280 -26.981 34.700 9.150 1.00 1.00NATOM 4861 CA ARG A1280 -27.561 34.508 10.472 1.00 1.00CATOM 4862 CARG A1280 -26.852 35.337 11.541 1.00 1.00CATOM 4863 OARG A1280 -26.796 36.531 11.341 1.00 1.00OATOM 4864 CB ARG A1280 -29.132 34.758 10.506 1.00 1.00CATOM 4865 CG ARG A1280 -29.881 34.295 11.779 1.00 1.00CATOM 4866 CD ARG A1280 -31.027 33.296 11.485 1.00 1.00CATOM 4867 NE ARG A1280 -30.568 32.038 10.855 1.00 1.00NATOM 4868 CZ ARG A1280 -31.330 31.094 10.461 1.00 1.00CATOM 4869 NH1 ARG A1280 -32.659 31.124 10.547 1.00 1.00NATOM 4870 NH2 ARG A1280 -30.810 30.013 9.918 1.00 1.00NATOM 4871 HA ARG A1280 -27.373 33.457 10.683 1.00 1.00HATOM 4872 HB1 ARG A1280 -29.623 34.288 9.668 1.00 1.00HATOM 4873 HB2 ARG A1280 -29.306 35.811 10.414 1.00 1.00HATOM 4874 HG1 ARG A1280 -29.128 33.779 12.441 1.00 1.00HATOM 4875 HG2 ARG A1280 -30.193 35.226 12.335 1.00 1.00HATOM 4876 HD1 ARG A1280 -31.409 33.099 12.485 1.00 1.00H
ATOM 4877 HD2 ARG A1280 -31.762 33.853 10.863 1.00 1.00 HATOM 4878 HE ARG A1280 -29.569 31.926 10.706 1.00 1.00 HATOM 4879 HH12 ARG A1280 -33.243 30.327 10.265 1.00 1.00 HATOM 4880 HH11 ARG A1280 -33.169 31.878 10.997 1.00 1.00 HATOM 4881 HH22 ARG A1280 -31.380 29.292 9.535 1.00 1.00 HATOM 4882 HH21 ARG A1280 -29.798 29.869 9.857 1.00 1.00 HATOM 4883 HN ARG A1280 -26.387 34.023 8.749 1.00 1.00 HATOM 4884 NPRO A1281 -26.232 34.822 12.622 1.00 1.00 NATOM 4885 CA PRO A1281 -26.173 33.406 12.934 1.00 1.00 CATOM 4886 CPRO A1281 -25.129 32.840 12.082 1.00 1.00 CATOM 4887 OPRO A1281 -24.527 33.527 11.249 1.00 1.00 OATOM 4888 CB PRO A1281 -25.770 33.527 14.449 1.00 1.00 CATOM 4889 CG PRO A1281 -24.763 34.737 14.388 1.00 1.00 CATOM 4890 CD PRO A1281 -25.546 35.737 13.526 1.00 1.00 CATOM 4891 HA PRO A1281 -27.069 32.853 12.847 1.00 1.00 HATOM 4892 HD2 PRO A1281 -24.912 36.493 13.042 1.00 1.00 HATOM 4893 HD1 PRO A1281 -26.295 36.311 14.117 1.00 1.00 HATOM 4894 HG2 PRO A1281 -23.853 34.527 13.890 1.00 1.00 HATOM 4895 HG1 PRO A1281 -24.536 35.126 15.392 1.00 1.00 HATOM 4896 HB1 PRO A1281 -26.669 33.840 15.024 1.00 1.00 HATOM 4897 HB2 PRO A1281 -25.316 32.650 14.914 1.00 1.00 HATOM 4898 NILE A1282 -24.846 31.537 12.266 1.00 1.00 NATOM 4899 CA ILE A1282 -23.810 30.838 11.489 1.00 1.00 CATOM 4900 CILE A1282 -24.490 29.970 10.437 1.00 1.00 CATOM 4901 OILE A1282 -24.272 28.768 10.407 1.00 1.00 OATOM 4902 CB ILE A1282 -22.785 30.072 12.346 1.00 1.00 CATOM 4903 CG1 ILE A1282 -22.350 30.966 13.551 1.00 1.00 CATOM 4904 CG2 ILE A1282 -21.588 29.657 11.506 1.00 1.00 CATOM 4905 CD1 ILE A1282 -21.409 30.255 14.535 1.00 1.00 CATOM 4906 HA ILE A1282 -23.193 31.650 10.949 1.00 1.00 HATOM 4907 HB ILE A1282 -23.201 29.188 12.872 1.00 1.00 HATOM 4908 HG11 ILE A1282 -21.840 31.868 13.147 1.00 1.00 HATOM 4909 HG12 ILE A1282 -23.266 31.263 14.120 1.00 1.00 HATOM 4910 HD11 ILE A1282 -21.481 30.761 15.516 1.00 1.00 HATOM 4911 HD12 ILE A1282 -21.639 29.125 14.694 1.00 1.00 HATOM 4912 HD13 ILE A1282 -20.369 30.325 14.136 1.00 1.00 HATOM 4913 HG21 ILE A1282 -20.854 29.038 12.065 1.00 1.00 HATOM 4914 HG22 ILE A1282 -21.099 30.560 11.107 1.00 1.00 HATOM 4915 HG23 ILE A1282 -21.922 29.083 10.634 1.00 1.00 HATOM 4916 HN ILE A1282 -25.356 30.916 12.888 1.00 1.00 HATOM 4917 NASP A1283 -25.353 30.588 9.630 1.00 1.00 NATOM 4918 CA ASP A1283 -25.942 29.814 8.537 1.00 1.00 CATOM 4919 CASP A1283 -24.818 29.383 7.572 1.00 1.00 CATOM 4920 OASP A1283 -24.874 28.307 7.014 1.00 1.00 OATOM 4921 CB ASP A1283 -27.009 30.600 7.815 1.00 1.00 CATOM 4922 CG ASP A1283 -28.119 31.135 8.667 1.00 1.00 CATOM 4923 OD1 ASP A1283 -28.398 30.693 9.815 1.00 1.00 OATOM 4924 OD2 ASP A1283 -28.864 32.100 8.281 1.00 1.00 OATOM 4925 HA ASP A1283 -26.528 28.925 8.905 1.00 1.00 HATOM 4926 HB1 ASP A1283 -26.524 31.439 7.337 1.00 1.00 HATOM 4927 HB2 ASP A1283 -27.482 29.955 7.068 1.00 1.00 HATOM 4928 HN ASP A1283 -25.513 31.584 9.624 1.00 1.00 H
ATOM 4929 N TRP A1284-23.721 30.235 7.313 1.00 1.00NATOM 4930 CA TRP A1284-22.729 29.896 6.261 1.00 1.00CATOM 4931 C TRP A1284-22.305 28.439 6.340 1.00 1.00CATOM 4932 O TRP A1284-22.266 27.642 5.401 1.00 1.00OATOM 4933 CB TRP A1284-21.542 30.912 6.364 1.00 1.00CATOM 4934 CG TRP A1284-20.588 30.909 5.219 1.00 1.00CATOM 4935 CD1 TRP A1284-20.707 30.214 4.098 1.00 1.00CATOM 4936 CD2 TRP A1284-19.335 31.722 5.085 1.00 1.00CATOM 4937 NE1 TRP A1284-19.700 30.533 3.260 1.00 1.00NATOM 4938 CE2 TRP A1284-18.909 31.469 3.803 1.00 1.00CATOM 4939 CE3 TRP A1284-18.654 32.635 5.885 1.00 1.00CATOM 4940 CZ2 TRP A1284-17.832 32.143 3.264 1.00 1.00CATOM 4941 CZ3 TRP A1284-17.571 33.368 5.369 1.00 1.00CATOM 4942 CH2 TRP A1284-17.174 33.098 4.063 1.00 1.00CATOM 4943 HA TRP A1284-23.203 29.936 5.285 1.00 1.00HATOM 4944 HB1 TRP A1284-21.947 31.904 6.409 1.00 1.00HATOM 4945 HB2 TRP A1284-21.051 30.760 7.316 1.00 1.00HATOM 4946 HE1 TRP A1284-19.602 30.180 2.304 1.00 1.00HATOM 4947 HD1 TRP A1284-21.451 29.468 3.810 1.00 1.00HATOM 4948 HZ2 TRP A1284-17.493 31.990 2.220 1.00 1.00HATOM 4949 HH2 TRP A1284-16.255 33.610 3.689 1.00 1.00HATOM 4950 HZ3 TRP A1284-17.109 34.134 6.001 1.00 1.00HATOM 4951 HE3 TRP A1284-18.998 32.828 6.925 1.00 1.00HATOM 4952 HN TRP A1284-23.697 31.162 7.700 1.00 1.00HATOM 4953 N LYS A1285-21.955 28.062 7.583 1.00 1.00NATOM 4954 CA LYS A1285-21.533 26.684 7.777 1.00 1.00CATOM 4955 C LYS A1285-22.606 25.619 7.405 1.00 1.00CATOM 4956 O LYS A1285-22.306 24.502 6.951 1.00 1.00OATOM 4957 CB LYS A1285-20.969 26.405 9.189 1.00 1.00CATOM 4958 CG LYS A1285-20.067 25.134 9.175 1.00 1.00CATOM 4959 CD LYS A1285-19.300 24.988 10.546 1.00 1.00CATOM 4960 CE LYS A1285-20.286 24.902 11.734 1.00 1.00CATOM 4961 NZ LYS A1285-19.555 24.619 13.019 1.00 1.00NATOM 4962 HA LYS A1285-20.715 26.518 7.090 1.00 1.00HATOM 4963 HB1 LYS A1285-20.315 27.235 9.562 1.00 1.00HATOM 4964 HB2 LYS A1285-21.813 26.314 9.860 1.00 1.00HATOM 4965 HG1 LYS A1285-20.758 24.307 8.949 1.00 1.00HATOM 4966 HG2 LYS A1285-19.312 25.149 8.374 1.00 1.00HATOM 4967 HD1 LYS A1285-18.622 24.104 10.463 1.00 1.00HATOM 4968 HD2 LYS A1285-18.680 25.857 10.708 1.00 1.00HATOM 4969 HE1 LYS A1285-20.908 25.852 11.809 1.00 1.00HATOM 4970 HE2 LYS A1285-21.049 24.174 11.540 1.00 1.00HATOM 4971 HZ1 LYS A1285-18.986 23.682 12.997 1.00 1.00HATOM 4972 HZ2 LYS A1285-18.904 25.452 13.305 1.00 1.00HATOM 4973 HZ3 LYS A1285-20.145 24.672 13.932 1.00 1.00HATOM 4974 HN LYS A1285-21.920 28.704 8.393 1.00 1.00HATOM 4975 N VAL A1286-23.912 25.892 7.722 1.00 1.00NATOM 4976 CA VAL A1286-24.941 24.887 7.381 1.00 1.00CATOM 4977 C VAL A1286-25.000 24.666 5.909 1.00 1.00CATOM 4978 O VAL A1286-25.057 23.503 5.535 1.00 1.00OATOM 4979 CB VAL A1286-26.369 24.928 8.015 1.00 1.00CATOM 4980 CG1 VAL A1286-26.278 25.212 9.554 1.00 1.00C
ATOM 4981 CG2 VAL A1286 -27.386 25.824 7.284 1.00 1.00CATOM 4982 HA VAL A1286 -24.502 23.895 7.686 1.00 1.00HATOM 4983 HB VAL A1286 -26.746 23.950 7.948 1.00 1.00HATOM 4984 HG11 VAL A1286 -25.456 24.579 9.967 1.00 1.00HATOM 4985 HG12 VAL A1286 -25.989 26.309 9.749 1.00 1.00HATOM 4986 HG13 VAL A1286 -27.223 25.031 10.104 1.00 1.00HATOM 4987 HG21 VAL A1286 -27.164 25.871 6.178 1.00 1.00HATOM 4988 HG22 VAL A1286 -28.473 25.508 7.527 1.00 1.00HATOM 4989 HG23 VAL A1286 -27.244 26.850 7.667 1.00 1.00HATOM 4990 HN VAL A1286 -24.200 26.780 8.013 1.00 1.00HATOM 4991 NCYS A1287 -24.882 25.584 4.956 1.00 1.00NATOM 4992 CA CYS A1287 -24.666 25.224 3.534 1.00 1.00CATOM 4993 CCYS A1287 -23.279 24.651 3.394 1.00 1.00CATOM 4994 OCYS A1287 -23.189 23.646 2.732 1.00 1.00OATOM 4995 CB CYS A1287 -24.803 26.428 2.546 1.00 1.00CATOM 4996 SG CYS A1287 -26.401 26.576 1.679 1.00 1.00SATOM 4997 HA CYS A1287 -25.421 24.464 3.303 1.00 1.00HATOM 4998 HB1 CYS A1287 -24.506 27.401 3.066 1.00 1.00HATOM 4999 HB2 CYS A1287 -24.092 26.152 1.726 1.00 1.00HATOM 5000 HN CYS A1287 -24.787 26.558 5.209 1.00 1.00HATOM 5001 NGLN A1288 -22.199 25.190 4.040 1.00 1.00NATOM 5002 CA GLN A1288 -20.889 24.505 3.872 1.00 1.00CATOM 5003 CGLN A1288 -20.953 22.968 4.034 1.00 1.00CATOM 5004 OGLN A1288 -20.626 22.242 3.088 1.00 1.00OATOM 5005 CB GLN A1288 -19.833 25.009 4.912 1.00 1.00CATOM 5006 CG GLN A1288 -18.351 24.690 4.566 1.00 1.00CATOM 5007 CD GLN A1288 -17.440 25.303 5.596 1.00 1.00CATOM 5008 OE1 GLN A1288 -17.929 26.122 6.376 1.00 1.00OATOM 5009 NE2 GLN A1288 -16.173 24.837 5.587 1.00 1.00NATOM 5010 HA GLN A1288 -20.377 24.727 2.887 1.00 1.00HATOM 5011 HB1 GLN A1288 -19.997 24.573 5.928 1.00 1.00HATOM 5012 HB2 GLN A1288 -20.005 26.076 5.038 1.00 1.00HATOM 5013 HG1 GLN A1288 -18.289 23.625 4.533 1.00 1.00HATOM 5014 HG2 GLN A1288 -18.085 24.965 3.553 1.00 1.00HATOM 5015 HE22 GLN A1288 -15.502 25.206 6.238 1.00 1.00HATOM 5016 HE21 GLN A1288 -15.880 24.085 5.031 1.00 1.00HATOM 5017 HN GLN A1288 -22.281 25.997 4.567 1.00 1.00HATOM 5018 NARG A1289 -21.392 22.473 5.191 1.00 1.00NATOM 5019 CA ARG A1289 -21.449 20.979 5.448 1.00 1.00CATOM 5020 CARG A1289 -22.850 20.434 5.293 1.00 1.00CATOM 5021 OARG A1289 -22.838 19.206 5.337 1.00 1.00OATOM 5022 CB ARG A1289 -20.782 20.562 6.807 1.00 1.00CATOM 5023 CG ARG A1289 -19.343 21.192 6.988 1.00 1.00CATOM 5024 CD ARG A1289 -18.291 21.005 5.872 1.00 1.00CATOM 5025 NE ARG A1289 -17.962 19.617 5.478 1.00 1.00NATOM 5026 CZ ARG A1289 -17.211 19.325 4.416 1.00 1.00CATOM 5027 NH1 ARG A1289 -16.627 20.215 3.647 1.00 1.00NATOM 5028 NH2 ARG A1289 -17.063 18.063 4.155 1.00 1.00NATOM 5029 HA ARG A1289 -20.833 20.443 4.754 1.00 1.00HATOM 5030 HB1 ARG A1289 -20.739 19.454 7.023 1.00 1.00HATOM 5031 HB2 ARG A1289 -21.432 20.968 7.605 1.00 1.00HATOM 5032 HG1 ARG A1289 -19.443 22.232 7.281 1.00 1.00H
ATOM 5033 HG2 ARG A1289 -18.833 20.651 7.843 1.00 1.00HATOM 5034 HD1 ARG A1289 -18.739 21.477 4.956 1.00 1.00HATOM 5035 HD2 ARG A1289 -17.316 21.491 6.091 1.00 1.00HATOM 5036 HE ARG A1289 -18.447 18.851 5.946 1.00 1.00HATOM 5037 HH12 ARG A1289 -16.147 19.911 2.804 1.00 1.00HATOM 5038 HH11 ARG A1289 -16.723 21.211 3.837 1.00 1.00HATOM 5039 HH22 ARG A1289 -16.578 17.777 3.316 1.00 1.00HATOM 5040 HH21 ARG A1289 -17.446 17.328 4.682 1.00 1.00HATOM 5041 HN ARG A1289 -21.746 23.047 5.935 1.00 1.00HATOM 5042 NILE A1290 -24.029 21.104 5.065 1.00 1.00NATOM 5043 CA ILE A1290 -25.199 20.409 4.492 1.00 1.00CATOM 5044 CILE A1290 -24.738 20.093 3.114 1.00 1.00CATOM 5045 OILE A1290 -24.827 18.945 2.738 1.00 1.00OATOM 5046 CB ILE A1290 -26.564 21.164 4.445 1.00 1.00CATOM 5047 CG1 ILE A1290 -27.144 21.374 5.911 1.00 1.00CATOM 5048 CG2 ILE A1290 -27.589 20.357 3.587 1.00 1.00CATOM 5049 CD1 ILE A1290 -28.258 22.462 5.926 1.00 1.00CATOM 5050 HA ILE A1290 -25.348 19.470 5.101 1.00 1.00HATOM 5051 HB ILE A1290 -26.421 22.203 3.996 1.00 1.00HATOM 5052 HG11 ILE A1290 -27.587 20.432 6.327 1.00 1.00HATOM 5053 HG12 ILE A1290 -26.308 21.737 6.585 1.00 1.00HATOM 5054 HD11 ILE A1290 -28.641 22.447 6.939 1.00 1.00HATOM 5055 HD12 ILE A1290 -29.036 22.304 5.151 1.00 1.00HATOM 5056 HD13 ILE A1290 -27.946 23.491 5.755 1.00 1.00HATOM 5057 HG21 ILE A1290 -27.167 19.995 2.670 1.00 1.00HATOM 5058 HG22 ILE A1290 -28.480 20.948 3.393 1.00 1.00HATOM 5059 HG23 ILE A1290 -27.894 19.413 4.137 1.00 1.00HATOM 5060 HN ILE A1290 -24.124 22.088 5.229 1.00 1.00HATOM 5061 NVAL A1291 -24.239 21.031 2.334 1.00 1.00NATOM 5062 CA VAL A1291 -23.758 20.681 0.964 1.00 1.00CATOM 5063 CVAL A1291 -22.719 19.577 1.056 1.00 1.00CATOM 5064 OVAL A1291 -22.837 18.617 0.321 1.00 1.00OATOM 5065 CB VAL A1291 -23.121 21.836 0.148 1.00 1.00CATOM 5066 CG1 VAL A1291 -22.367 21.316 -1.151 1.00 1.00CATOM 5067 CG2 VAL A1291 -24.145 22.950 -0.186 1.00 1.00CATOM 5068 HA VAL A1291 -24.658 20.317 0.330 1.00 1.00HATOM 5069 HB VAL A1291 -22.349 22.272 0.752 1.00 1.00HATOM 5070 HG11 VAL A1291 -21.924 22.095 -1.786 1.00 1.00HATOM 5071 HG12 VAL A1291 -21.578 20.572 -0.957 1.00 1.00HATOM 5072 HG13 VAL A1291 -23.140 20.784 -1.738 1.00 1.00HATOM 5073 HG21 VAL A1291 -24.961 22.541 -0.786 1.00 1.00HATOM 5074 HG22 VAL A1291 -24.553 23.343 0.731 1.00 1.00HATOM 5075 HG23 VAL A1291 -23.695 23.764 -0.752 1.00 1.00HATOM 5076 HN VAL A1291 -24.072 21.937 2.683 1.00 1.00HATOM 5077 NGLY A1292 -21.680 19.743 1.925 1.00 1.00NATOM 5078 CA GLY A1292 -20.756 18.618 2.128 1.00 1.00CATOM 5079 CGLY A1292 -21.518 17.368 2.405 1.00 1.00CATOM 5080 OGLY A1292 -21.404 16.429 1.654 1.00 1.00OATOM 5081 HA2 GLY A1292 -20.090 18.886 2.900 1.00 1.00HATOM 5082 HA1 GLY A1292 -20.189 18.685 1.202 1.00 1.00HATOM 5083 HN GLY A1292 -21.547 20.589 2.495 1.00 1.00HATOM 5084 NLEU A1293 -22.288 17.318 3.509 1.00 1.00N
ATOM 5085 CA LEU A1293 -22.853 16.043 3.938 1.00 1.00CATOM 5086 C LEU A1293 -23.660 15.500 2.777 1.00 1.00CATOM 5087 O LEU A1293 -23.602 14.291 2.562 1.00 1.00OATOM 5088 CB LEU A1293 -23.786 16.313 5.181 1.00 1.00CATOM 5089 CG LEU A1293 -24.323 14.954 5.735 1.00 1.00CATOM 5090 CD1LEU A1293 -23.229 13.957 6.249 1.00 1.00CATOM 5091 CD2LEU A1293 -25.425 15.232 6.797 1.00 1.00CATOM 5092 HA LEU A1293 -22.039 15.362 4.191 1.00 1.00HATOM 5093 HB1LEU A1293 -24.578 16.981 4.837 1.00 1.00HATOM 5094 HB2LEU A1293 -23.295 16.857 5.993 1.00 1.00HATOM 5095 HG LEU A1293 -24.926 14.462 4.932 1.00 1.00HATOM 5096 HD21 LEU A1293 -25.898 14.249 7.026 1.00 1.00HATOM 5097 HD22 LEU A1293 -24.960 15.651 7.725 1.00 1.00HATOM 5098 HD23 LEU A1293 -26.201 15.951 6.435 1.00 1.00HATOM 5099 HD11 LEU A1293 -22.687 13.486 5.449 1.00 1.00HATOM 5100 HD12 LEU A1293 -22.495 14.505 6.842 1.00 1.00HATOM 5101 HD13 LEU A1293 -23.727 13.212 6.853 1.00 1.00HATOM 5102 HN LEU A1293 -22.372 18.140 4.079 1.00 1.00HATOM 5103 N LEU A1294 -24.387 16.328 1.962 1.00 1.00NATOM 5104 CA LEU A1294 -25.163 15.668 0.916 1.00 1.00CATOM 5105 C LEU A1294 -24.195 14.975 -0.083 1.00 1.00CATOM 5106 O LEU A1294 -24.331 13.816 -0.397 1.00 1.00OATOM 5107 CB LEU A1294 -26.218 16.551 0.156 1.00 1.00CATOM 5108 CG LEU A1294 -27.019 15.788 -0.933 1.00 1.00CATOM 5109 CD1LEU A1294 -28.049 14.762 -0.438 1.00 1.00CATOM 5110 CD2LEU A1294 -27.829 16.828 -1.784 1.00 1.00CATOM 5111 HA LEU A1294 -25.828 14.912 1.343 1.00 1.00HATOM 5112 HB1LEU A1294 -25.616 17.340 -0.349 1.00 1.00HATOM 5113 HB2LEU A1294 -26.942 17.032 0.829 1.00 1.00HATOM 5114 HG LEU A1294 -26.377 15.136 -1.568 1.00 1.00HATOM 5115 HD21 LEU A1294 -28.414 16.337 -2.587 1.00 1.00HATOM 5116 HD22 LEU A1294 -28.587 17.436 -1.216 1.00 1.00HATOM 5117 HD23 LEU A1294 -27.113 17.569 -2.229 1.00 1.00HATOM 5118 HD11 LEU A1294 -28.664 15.362 0.202 1.00 1.00HATOM 5119 HD12 LEU A1294 -28.591 14.307 -1.290 1.00 1.00HATOM 5120 HD13 LEU A1294 -27.589 13.884 0.100 1.00 1.00HATOM 5121 HN LEU A1294 -24.496 17.321 2.088 1.00 1.00HATOM 5122 N GLY A1295 -23.225 15.729 -0.655 1.00 1.00NATOM 5123 CA GLY A1295 -22.317 15.047 -1.600 1.00 1.00CATOM 5124 C GLY A1295 -21.521 13.872 -0.969 1.00 1.00CATOM 5125 O GLY A1295 -21.392 12.842 -1.610 1.00 1.00OATOM 5126 HA2GLY A1295 -21.531 15.810 -1.917 1.00 1.00HATOM 5127 HA1GLY A1295 -22.772 14.705 -2.529 1.00 1.00HATOM 5128 HN GLY A1295 -23.065 16.709 -0.403 1.00 1.00HATOM 5129 N PHE A1296 -21.035 14.020 0.272 1.00 1.00NATOM 5130 CA PHE A1296 -20.367 12.901 0.937 1.00 1.00CATOM 5131 C PHE A1296 -21.308 11.818 1.459 1.00 1.00CATOM 5132 O PHE A1296 -20.882 10.686 1.508 1.00 1.00OATOM 5133 CB PHE A1296 -19.471 13.486 2.037 1.00 1.00CATOM 5134 CG PHE A1296 -18.879 12.326 2.879 1.00 1.00CATOM 5135 CD1PHE A1296 -17.816 11.596 2.337 1.00 1.00CATOM 5136 CD2PHE A1296 -19.393 12.034 4.151 1.00 1.00C
ATOM 5137 CE1 PHE A1296 -17.387 10.456 2.964 1.00 1.00CATOM 5138 CE2 PHE A1296 -18.809 10.971 4.840 1.00 1.00CATOM 5139 CZ PHE A1296 -17.851 10.152 4.254 1.00 1.00CATOM 5140 HA PHE A1296 -19.732 12.341 0.210 1.00 1.00HATOM 5141 HB1 PHE A1296 -20.116 14.119 2.688 1.00 1.00HATOM 5142 HB2 PHE A1296 -18.763 14.124 1.499 1.00 1.00HATOM 5143 HD2 PHE A1296 -20.206 12.582 4.623 1.00 1.00HATOM 5144 HE2 PHE A1296 -19.057 10.723 5.856 1.00 1.00HATOM 5145 HZ PHE A129617.494 9.3024.804 1.00 1.00HATOM 5146 HE1 PHE A1296 -16.664 9.8622.404 1.00 1.00HATOM 5147 HD1 PHE A1296 -17.317 11.922 1.440 1.00 1.00HATOM 5148 HN PHE A1296 -21.241 14.818 0.840 1.00 1.00HATOM 5149 NALA A1297 -22.562 12.097 1.878 1.00 1.00NATOM 5150 CA ALA A1297 -23.413 11.025 2.368 1.00 1.00CATOM 5151 CALA A1297 -24.054 10.314 1.244 1.00 1.00CATOM 5152 OALA A1297 -24.071 9.0851.299 1.00 1.00OATOM 5153 CB ALA A1297 -24.579 11.506 3.256 1.00 1.00CATOM 5154 HA ALA A1297 -22.846 10.374 3.041 1.00 1.00HATOM 5155 HB1 ALA A1297 -25.266 10.703 3.651 1.00 1.00HATOM 5156 HB2 ALA A1297 -24.142 12.032 4.124 1.00 1.00HATOM 5157 HB3 ALA A1297 -25.086 12.269 2.636 1.00 1.00HATOM 5158 HN ALA A1297 -22.910 13.051 1.858 1.00 1.00HATOM 5159 NALA A1298 -24.555 10.972 0.170 1.00 1.00NATOM 5160 CA ALA A1298 -25.210 10.256 -0.945 1.00 1.00CATOM 5161 CALA A1298 -24.470 8.996 -1.349 1.00 1.00CATOM 5162 OALA A1298 -25.143 7.965 -1.331 1.00 1.00OATOM 5163 CB ALA A1298 -25.423 11.143 -2.207 1.00 1.00CATOM 5164 HA ALA A1298 -26.212 9.912 -0.647 1.00 1.00HATOM 5165 HB1 ALA A1298 -25.717 10.662 -3.116 1.00 1.00HATOM 5166 HB2 ALA A1298 -26.154 11.910 -1.990 1.00 1.00HATOM 5167 HB3 ALA A1298 -24.536 11.685 -2.406 1.00 1.00HATOM 5168 HN ALA A1298 -24.448 11.946 0.093 1.00 1.00HATOM 5169 NPRO A1299 -23.165 8.930 -1.686 1.00 1.00NATOM 5170 CA PRO A1299 -22.610 7.606 -1.942 1.00 1.00CATOM 5171 CPRO A1299 -22.766 6.828 -0.660 1.00 1.00CATOM 5172 OPRO A1299 -23.394 5.773 -0.717 1.00 1.00OATOM 5173 CB PRO A1299 -21.130 8.014 -2.205 1.00 1.00CATOM 5174 CG PRO A1299 -20.921 9.287 -1.426 1.00 1.00CATOM 5175 CD PRO A1299 -22.266 10.052 -1.590 1.00 1.00CATOM 5176 HA PRO A1299 -23.038 7.151 -2.833 1.00 1.00HATOM 5177 HD2 PRO A1299 -22.467 10.718 -0.735 1.00 1.00HATOM 5178 HD1 PRO A1299 -22.232 10.660 -2.522 1.00 1.00HATOM 5179 HG2 PRO A1299 -20.077 9.958 -1.715 1.00 1.00HATOM 5180 HG1 PRO A1299 -20.796 9.026 -0.406 1.00 1.00HATOM 5181 HB1 PRO A1299 -20.955 8.397 -3.271 1.00 1.00HATOM 5182 HB2 PRO A1299 -20.384 7.217 -1.913 1.00 1.00HATOM 5183 H31 PRO A1299 -22.431 7.0500.365 1.00 1.00HTERATOM 5184 PGB 19.97818.634 9.126 1.00 1.00PATOM 5185 O1P GB 110.277 17.475 9.966 1.00 1.00OATOM 5186 O2P GB 110.102 18.062 7.766 1.00 1.00OATOM 5187 O5*GB 18.51019.136 9.514 1.00 1.00O
ATOM 5188 C5*GB 1 8.248 19.280 10.931 1.00 1.00 CATOM 5189 C4*GB 1 6.746 19.746 11.168 1.00 1.00 CATOM 5190 O4*GB 1 6.518 19.998 12.557 1.00 1.00 OATOM 5191 C1*GB 1 5.335 20.855 12.697 1.00 1.00 CATOM 5192 C2*GB 1 5.612 21.906 11.578 1.00 1.00 CATOM 5193 C3*GB 1 6.415 21.088 10.493 1.00 1.00 CATOM 5194 O3*GB 1 5.718 20.964 9.2651.00 1.00 OATOM 5195 N9GB 1 5.412 21.337 14.003 1.00 1.00 NATOM 5196 C8GB 1 5.143 22.572 14.356 1.00 1.00 CATOM 5197 N7GB 1 5.247 22.678 15.573 1.00 1.00 NATOM 5198 C5GB 1 5.683 21.440 16.154 1.00 1.00 CATOM 5199 O6GB 1 5.978 21.702 18.480 1.00 1.00 OATOM 5200 C6GB 1 6.043 20.972 17.505 1.00 1.00 CATOM 5201 N1GB 1 6.476 19.724 17.548 1.00 1.00 NATOM 5202 N2GB 1 6.914 17.651 16.668 1.00 1.00 NATOM 5203 C2GB 1 6.528 18.879 16.468 1.00 1.00 CATOM 5204 N3GB 1 6.179 19.274 15.283 1.00 1.00 NATOM 5205 C4GB 1 5.768 20.640 15.077 1.00 1.00 CATOM 5206 H5*1 GB 1 8.998 20.043 11.193 1.00 1.00 HATOM 5207 H5*2 GB 1 8.486 18.304 11.400 1.00 1.00 HATOM 5208 H4*GB 1 6.016 18.952 10.935 1.00 1.00 HATOM 5209 H1*GB 1 4.424 20.186 12.584 1.00 1.00 HATOM 5210 H2*1 GB 1 4.666 22.418 11.192 1.00 1.00 HATOM 5211 H2*2 GB 1 6.285 22.640 12.065 1.00 1.00 HATOM 5212 H3*GB 1 7.347 21.621 10.220 1.00 1.00 HATOM 5213 H8GB 1 4.823 23.435 13.769 1.00 1.00 HATOM 5214 H1GB 1 6.878 19.425 18.396 1.00 1.00 HATOM 5215 H21 GB 1 6.964 16.996 15.892 1.00 1.00 HATOM 5216 H22 GB 1 7.155 17.326 17.602 1.00 1.00 HATOM 5217 H7GB 1 10.699 19.344 9.2201.00 1.00 HATOM 5218 P CB 2 4.267 20.344 9.0041.00 1.00 PATOM 5219 O1P CB 2 3.540 20.364 10.306 1.00 1.00 OATOM 5220 O2P CB 2 4.527 18.955 8.5321.00 1.00 OATOM 5221 O5*CB 2 3.530 21.270 7.8151.00 1.00 OATOM 5222 C5*CB 2 3.449 20.849 6.4331.00 1.00 CATOM 5223 C4*CB 2 2.281 19.883 6.0911.00 1.00 CATOM 5224 O4*CB 2 2.138 18.943 7.1351.00 1.00 OATOM 5225 C1*CB 2 0.717 18.660 7.2921.00 1.00 CATOM 5226 C2*CB 2 0.259 20.093 7.2621.00 1.00 CATOM 5227 C3*CB 2 0.885 20.556 5.9461.00 1.00 CATOM 5228 O3*CB 2 0.194 19.995 4.7831.00 1.00 OATOM 5229 N1CB 2 0.191 18.057 8.5051.00 1.00 NATOM 5230 C6CB 2 1.013 17.927 9.6081.00 1.00 CATOM 5231 C5CB 2 0.476 17.687 10.797 1.00 1.00 CATOM 5232 N4CB 2 -1.449 17.099 12.119 1.00 1.00 NATOM 5233 C4CB 2 -0.988 17.392 10.928 1.00 1.00 CATOM 5234 N3CB 2 -1.705 17.494 9.9171.00 1.00 NATOM 5235 O2CB 2 -1.942 17.972 7.7421.00 1.00 OATOM 5236 C2CB 2 -1.144 17.855 8.6191.00 1.00 CATOM 5237 H5*1 CB 2 4.388 20.292 6.1981.00 1.00 HATOM 5238 H5*2 CB 2 3.339 21.768 5.8451.00 1.00 HATOM 5239 H4*CB 2 2.440 19.341 5.1531.00 1.00 H
ATOM 5240 H1*CB 2 0.443 18.085 6.408 1.00 1.00HATOM 5241 H2*1 CB 2 -0.852 20.244 7.232 1.00 1.00HATOM 5242 H2*2 CB 2 0.620 20.576 8.166 1.00 1.00HATOM 5243 H3*CB 2 0.944 21.697 5.877 1.00 1.00HATOM 5244 H6CB 2 2.077 18.043 9.585 1.00 1.00HATOM 5245 H5CB 2 1.051 17.689 11.755 1.00 1.00HATOM 5246 H41 CB 2 -2.492 16.979 12.204 1.00 1.00HATOM 5247 H42 CB 2 -0.832 17.071 12.983 1.00 1.00HATOM 5248 P TB 3 0.531 20.461 3.283 1.00 1.00PATOM 5249 O1P TB 3 1.714 21.375 3.428 1.00 1.00OATOM 5250 O2P TB 3 -0.563 21.190 2.607 1.00 1.00OATOM 5251 O5*TB 3 0.867 19.198 2.338 1.00 1.00OATOM 5252 C5*TB 3 2.104 19.085 1.624 1.00 1.00CATOM 5253 C4*TB 3 2.230 17.859 0.722 1.00 1.00CATOM 5254 O4*TB 3 1.867 16.569 1.217 1.00 1.00OATOM 5255 Cl*TB 3 1.388 15.704 0.194 1.00 1.00CATOM 5256 C2*TB 3 1.647 16.528 -1.104 1.00 1.00CATOM 5257 C3*TB 3 1.498 17.993 -0.621 1.00 1.00CATOM 5258 O3*TB 3 2.178 18.878 -1.514 1.00 1.00OATOM 5259 N1TB 3 -0.073 15.623 0.222 1.00 1.00NATOM 5260 C2TB 3 -0.638 14.661 -0.549 1.00 1.00CATOM 5261 N3TB 3 -1.957 14.543 -0.598 1.00 1.00NATOM 5262 C4TB 3 -2.745 15.471 0.002 1.00 1.00CATOM 5263 C5TB 3 -2.177 16.579 0.805 1.00 1.00CATOM 5264 C6TB 3 -0.822 16.506 0.920 1.00 1.00CATOM 5265 O2TB 3 0.061 13.901 -1.193 1.00 1.00OATOM 5266 O4TB 3 -3.954 15.429 -0.123 1.00 1.00OATOM 5267 H5*1 TB 3 2.902 19.048 2.380 1.00 1.00HATOM 5268 H5*2 TB 3 2.172 20.025 1.032 1.00 1.00HATOM 5269 H4*TB 3 3.290 17.742 0.435 1.00 1.00HATOM 5270 H1*TB 3 1.883 14.726 0.261 1.00 1.00HATOM 5271 H2*1 TB 3 2.665 16.338 -1.409 1.00 1.00HATOM 5272 H2*2 TB 3 0.940 16.332 -1.878 1.00 1.00HATOM 5273 H3*TB 3 0.444 18.369 -0.486 1.00 1.00HATOM 5274 C5M TB 3 -2.995 17.692 1.395 1.00 1.00CATOM 5275 H3TB 3 -2.354 13.838 -1.154 1.00 1.00HATOM 5276 H6TB 3 -0.396 17.254 1.605 1.00 1.00HATOM 5277 H51 TB 3 -2.442 18.470 1.922 1.00 1.00HATOM 5278 H52 TB 3 -3.470 18.142 0.549 1.00 1.00HATOM 5279 H53 TB 3 -3.669 17.252 2.154 1.00 1.00HATOM 5280 P CB 4 1.561 19.388 -2.878 1.00 1.00PATOM 5281 O1P CB 4 2.677 20.130 -3.600 1.00 1.00OATOM 5282 O2P CB 4 0.383 20.212 -2.556 1.00 1.00OATOM 5283 O5*CB 4 1.047 18.176 -3.736 1.00 1.00OATOM 5284 C5*CB 4 2.000 17.454 -4.536 1.00 1.00CATOM 5285 C4*CB 4 1.184 16.382 -5.282 1.00 1.00CATOM 5286 O4*CB 4 0.388 15.518 -4.414 1.00 1.00OATOM 5287 C1*CB 4 -0.688 14.937 -5.214 1.00 1.00CATOM 5288 C2*CB 4 -0.631 15.630 -6.572 1.00 1.00CATOM 5289 C3*CB 4 0.117 16.950 -6.225 1.00 1.00CATOM 5290 O3*CB 4 0.785 17.584 -7.342 1.00 1.00OATOM 5291 N1CB 4 -1.934 15.167 -4.500 1.00 1.00N
ATOM 5292 C6CB 4 -2.059 16.149 -3.529 1.00 1.00 CATOM 5293 C5CB 4 -3.193 16.353 -2.851 1.00 1.00 CATOM 5294 N4CB 4 -5.517 15.681 -2.416 1.00 1.00 NATOM 5295 C4CB 4 -4.389 15.482 -3.064 1.00 1.00 CATOM 5296 N3CB 4 -4.253 14.585 -3.968 1.00 1.00 NATOM 5297 O2CB 4 -3.029 13.620 -5.620 1.00 1.00 OATOM 5298 C2CB 4 -3.030 14.446 -4.755 1.00 1.00 CATOM 5299 H5*1 CB 42.709 16.938 -3.850 1.00 1.00 HATOM 5300 H5*2 CB 42.618 18.047 -5.232 1.00 1.00 HATOM 5301 H4*CB 41.816 15.761 -5.860 1.00 1.00 HATOM 5302 H1*CB 4 -0.404 13.904 -5.379 1.00 1.00 HATOM 5303 H2*1 CB 4 -0.113 15.024 -7.307 1.00 1.00 HATOM 5304 H2*2 CB 4 -1.598 15.862 -7.024 1.00 1.00 HATOM 5305 H3*CB 4 -0.515 17.660 -5.704 1.00 1.00 HATOM 5306 H6CB 4 -1.232 16.784 -3.287 1.00 1.00 HATOM 5307 H5CB 4 -3.265 17.160 -2.124 1.00 1.00 HATOM 5308 H41 CB 4 -6.260 15.014 -2.594 1.00 1.00 HATOM 5309 H42 CB 4 -5.629 16.394 -1.695 1.00 1.00 HATOM 5310 P CB 5 -0.082 18.421 -8.434 1.00 1.00 PATOM 5311 O1P CB 50.753 19.086 -9.468 1.00 1.00 OATOM 5312 O2P CB 5 -0.938 19.477 -7.812 1.00 1.00 OATOM 5313 O5*CB 5 -1.252 17.568 -9.193 1.00 1.00 OATOM 5314 C5*CB 5 -0.945 16.544 -10.159 1.00 1.00 CATOM 5315 C4*CB 5 -2.253 15.860 -10.519 1.00 1.00 CATOM 5316 O4*CB 5 -2.788 15.182 -9.353 1.00 1.00 OATOM 5317 C1*CB 5 -4.211 15.075 -9.504 1.00 1.00 CATOM 5318 C2*CB 5 -4.606 15.929 -10.715 1.00 1.00 CATOM 5319 C3*CB 5 -3.400 16.849 -10.827 1.00 1.00 CATOM 5320 O3*CB 5 -3.195 17.595 -12.046 1.00 1.00 OATOM 5321 N1CB 5 -4.866 15.581 -8.255 1.00 1.00 NATOM 5322 C6CB 5 -4.260 16.608 -7.510 1.00 1.00 CATOM 5323 C5CB 5 -4.745 16.993 -6.318 1.00 1.00 CATOM 5324 N4CB 5 -6.514 16.782 -4.720 1.00 1.00 NATOM 5325 C4CB 5 -5.986 16.360 -5.816 1.00 1.00 CATOM 5326 N3CB 5 -6.565 15.501 -6.568 1.00 1.00 NATOM 5327 O2CB 5 -6.532 14.166 -8.366 1.00 1.00 OATOM 5328 C2CB 5 -5.951 15.023 -7.758 1.00 1.00 CATOM 5329 H5*1 CB 5 -0.240 15.825 -9.713 1.00 1.00 HATOM 5330 H5*2 CB 5 -0.456 17.026 -11.048 1.00 1.00 HATOM 5331 H4*CB 5 -2.112 15.168 -11.381 1.00 1.00 HATOM 5332 H1*CB 5 -4.475 14.004 -9.663 1.00 1.00 HATOM 5333 H2*1 CB 5 -4.669 15.306 -11.628 1.00 1.00 HATOM 5334 H2*2 CB 5 -5.536 16.501 -10.550 1.00 1.00 HATOM 5335 H3*CB 5 -3.591 17.543 -9.995 1.00 1.00 HATOM 5336 H6CB 5 -3.337 17.169 -7.851 1.00 1.00 HATOM 5337 H5CB 5 -4.194 17.786 -5.803 1.00 1.00 HATOM 5338 H41 CB 5 -7.404 16.352 -4.396 1.00 1.00 HATOM 5339 H42 CB 5 -6.101 17.579 -4.246 1.00 1.00 HATOM 5340 P GB 6 -4.141 18.837 -12.375 1.00 1.00 PATOM 5341 O1P GB 6 -3.892 19.366 -13.746 1.00 1.00 OATOM 5342 O2P GB 6 -3.858 19.867 -11.325 1.00 1.00 OATOM 5343 O5*GB 6 -5.626 18.343 -12.302 1.00 1.00 O
ATOM 5344 C5*GB 6 -6.04217.556 -13.417 1.00 1.00CATOM 5345 C4*GB 6 -7.46017.098 -13.243 1.00 1.00CATOM 5346 O4*GB 6 -7.64916.422 -12.004 1.00 1.00OATOM 5347 C1*GB 6 -9.01216.648 -11.571 1.00 1.00CATOM 5348 C2*GB 6 -9.66517.662 -12.569 1.00 1.00CATOM 5349 C3*GB 6 -8.39918.287 -13.229 1.00 1.00CATOM 5350 O3*GB 6 -8.61318.684 -14.589 1.00 1.00OATOM 5351 N9GB 6 -9.00717.278 -10.242 1.00 1.00NATOM 5352 C8GB 6 -8.00217.936 -9.7621.00 1.00CATOM 5353 N7GB 6 -8.24318.346 -8.6131.00 1.00NATOM 5354 C5GB 6 -9.54717.905 -8.2291.00 1.00CATOM 5355 O6GB 6 -10.018 18.697 -6.1171.00 1.00OATOM 5356 C6GB 6 -10.426 18.019 -7.0541.00 1.00CATOM 5357 N1GB 6 -11.585 17.363 -7.1211.00 1.00NATOM 5358 N2GB 6 -13.217 16.295 -8.3501.00 1.00NATOM 5359 C2GB 6 -12.001 16.769 -8.2781.00 1.00CATOM 5360 N3GB 6 -11.237 16.666 -9.2951.00 1.00NATOM 5361 C4GB 6 -9.90117.258 -9.3111.00 1.00CATOM 5362 H5*1 GB 6 -5.42416.682 -13.501 1.00 1.00HATOM 5363 H5*2 GB 6 -5.91318.140 -14.341 1.00 1.00HATOM 5364 H4*GB 6 -7.85616.388 -13.972 1.00 1.00HATOM 5365 H1*GB 6 -9.59015.714 -11.561 1.00 1.00HATOM 5366 H2*1 GB 6 -10.202 17.179 -13.354 1.00 1.00HATOM 5367 H2*2 GB 6 -10.335 18.377 -12.078 1.00 1.00HATOM 5368 H3*GB 6 -8.03519.065 -12.481 1.00 1.00HATOM 5369 H8GB 6 -7.05018.175 -10.196 1.00 1.00HATOM 5370 H1GB 6 -12.148 17.353 -6.3081.00 1.00HATOM 5371 H21 GB 6 -13.585 15.802 -9.2361.00 1.00HATOM 5372 H22 GB 6 -13.840 16.331 -7.5441.00 1.00HATOM 5373 P GB 7 -9.38120.019 -15.030 1.00 1.00PATOM 5374 O1P GB 7 -9.38320.234 -16.502 1.00 1.00OATOM 5375 O2P GB 7 -8.63621.113 -14.333 1.00 1.00OATOM 5376 O5*GB 7 -10.895 20.032 -14.650 1.00 1.00OATOM 5377 C5*GB 7 -11.912 19.244 -15.204 1.00 1.00CATOM 5378 C4*GB 7 -13.143 19.170 -14.242 1.00 1.00CATOM 5379 O4*GB 7 -12.862 18.629 -12.908 1.00 1.00OATOM 5380 C1*GB 7 -13.712 19.248 -11.948 1.00 1.00CATOM 5381 C2*GB 7 -14.637 20.219 -12.763 1.00 1.00CATOM 5382 C3*GB 7 -13.666 20.583 -13.910 1.00 1.00CATOM 5383 O3*GB 7 -14.394 21.039 -15.085 1.00 1.00OATOM 5384 N9GB 7 -12.822 19.896 -10.989 1.00 1.00NATOM 5385 C8GB 7 -11.666 20.404 -11.172 1.00 1.00CATOM 5386 N7GB 7 -11.146 20.780 -10.079 1.00 1.00NATOM 5387 C5GB 7 -12.153 20.611 -9.0541.00 1.00CATOM 5388 O6GB 7 -11.342 21.402 -7.0461.00 1.00OATOM 5389 C6GB 7 -12.325 20.932 -7.6421.00 1.00CATOM 5390 N1GB 7 -13.586 20.654 -7.1421.00 1.00NATOM 5391 N2GB 7 -15.788 20.065 -7.3131.00 1.00NATOM 5392 C2GB 7 -14.613 20.196 -7.8871.00 1.00CATOM 5393 N3GB 7 -14.428 19.864 -9.0771.00 1.00NATOM 5394 C4GB 7 -13.140 20.057 -9.7401.00 1.00CATOM 5395 H5*1 GB 7 -11.488 18.243 -15.345 1.00 1.00H
ATOM 5396 H5*2 GB 7 -12.200 19.667 -16.154 1.00 1.00HATOM 5397 H4*GB 7 -13.884 18.515 -14.728 1.00 1.00HATOM 5398 H1*GB 7 -14.276 18.485 -11.444 1.00 1.00HATOM 5399 H2*1 GB 7 -15.524 19.683 -13.102 1.00 1.00HATOM 5400 H2*2 GB 7 -14.974 21.042 -12.106 1.00 1.00HATOM 5401 H3*GB 7 -12.801 21.258 -13.602 1.00 1.00HATOM 5402 H8GB 7 -11.021 20.576 -12.017 1.00 1.00HATOM 5403 H1GB 7 -13.731 20.886 -6.174 1.00 1.00HATOM 5404 H21 GB 7 -16.529 19.735 -7.918 1.00 1.00HATOM 5405 H22 GB 7 -15.973 20.310 -6.337 1.00 1.00HATOM 5406 P CB 8 -15.013 22.538 -15.034 1.00 1.00PATOM 5407 O1P CB 8 -16.043 22.433 -16.113 1.00 1.00OATOM 5408 O2P CB 8 -13.947 23.570 -15.359 1.00 1.00OATOM 5409 O5*CB 8 -15.783 22.905 -13.691 1.00 1.00OATOM 5410 C5*CB 8 -17.195 22.716 -13.384 1.00 1.00CATOM 5411 C4*CB 8 -17.523 23.090 -11.904 1.00 1.00CATOM 5412 O4*CB 8 -16.493 22.558 -11.084 1.00 1.00OATOM 5413 C1*CB 8 -16.378 23.332 -9.935 1.00 1.00CATOM 5414 C2*CB 8 -16.908 24.778 -10.308 1.00 1.00CATOM 5415 C3*CB 8 -17.317 24.596 -11.774 1.00 1.00CATOM 5416 O3*CB 8 -18.514 25.243 -12.158 1.00 1.00OATOM 5417 N1CB 8 -14.975 23.496 -9.588 1.00 1.00NATOM 5418 C6CB 8 -14.006 23.448 -10.525 1.00 1.00CATOM 5419 C5CB 8 -12.708 23.571 -10.200 1.00 1.00CATOM 5420 N4CB 8 -11.045 23.957 -8.560 1.00 1.00NATOM 5421 C4CB 8 -12.314 23.881 -8.840 1.00 1.00CATOM 5422 N3CB 8 -13.228 23.990 -7.980 1.00 1.00NATOM 5423 O2CB 8 -15.439 23.995 -7.385 1.00 1.00OATOM 5424 C2CB 8 -14.646 23.864 -8.319 1.00 1.00CATOM 5425 H5*1 CB 8 -17.328 21.646 -13.529 1.00 1.00HATOM 5426 H5*2 CB 8 -17.927 23.210 -14.046 1.00 1.00HATOM 5427 H4*CB 8 -18.572 22.879 -11.608 1.00 1.00HATOM 5428 H1*CB 8 -16.927 22.835 -9.149 1.00 1.00HATOM 5429 H2*1 CB 8 -17.732 24.903 -9.615 1.00 1.00HATOM 5430 H2*2 CB 8 -16.148 25.607 -10.341 1.00 1.00HATOM 5431 H3*CB 8 -16.564 24.948 -12.437 1.00 1.00HATOM 5432 H6CB 8 -14.227 23.270 -11.602 1.00 1.00HATOM 5433 H5CB 8 -11.974 23.522 -11.001 1.00 1.00HATOM 5434 H41 CB 8 -10.754 24.151 -7.564 1.00 1.00HATOM 5435 H42 CB 8 -10.281 23.841 -9.293 1.00 1.00HATOM 5436 P GB 9 -18.789 26.828 -12.316 1.00 1.00PATOM 5437 O1P GB 9 -20.178 27.026 -12.741 1.00 1.00OATOM 5438 O2P GB 9 -17.741 27.664 -12.965 1.00 1.00OATOM 5439 O5*GB 9 -18.832 27.287 -10.786 1.00 1.00OATOM 5440 C5*GB 9 -19.889 27.068 -9.894 1.00 1.00CATOM 5441 C4*GB 9 -19.641 27.900 -8.611 1.00 1.00CATOM 5442 O4*GB 9 -18.346 27.598 -8.073 1.00 1.00OATOM 5443 C1*GB 9 -17.591 28.747 -7.830 1.00 1.00CATOM 5444 C2*GB 9 -18.220 29.831 -8.743 1.00 1.00CATOM 5445 C3*GB 9 -19.695 29.399 -8.929 1.00 1.00CATOM 5446 O3*GB 9 -20.601 30.061 -8.001 1.00 1.00OATOM 5447 N9GB 9 -16.203 28.325 -8.032 1.00 1.00N
ATOM 5448 C8GB 9 -15.746 28.016 -9.201 1.00 1.00CATOM 5449 N7GB 9 -14.519 27.739 -9.094 1.00 1.00NATOM 5450 C5GB 9 -14.086 27.936 -7.742 1.00 1.00CATOM 5451 O6GB 9 -11.796 27.602 -7.445 1.00 1.00OATOM 5452 C6GB 9 -12.856 27.908 -6.922 1.00 1.00CATOM 5453 N1GB 9 -12.987 28.216 -5.621 1.00 1.00NATOM 5454 N2GB 9 -14.134 28.801 -3.738 1.00 1.00NATOM 5455 C2GB 9 -14.102 28.544 -5.021 1.00 1.00CATOM 5456 N3GB 9 -15.189 28.579 -5.707 1.00 1.00NATOM 5457 C4GB 9 -15.200 28.314 -7.138 1.00 1.00CATOM 5458 H5*1 GB 9 -19.897 26.001 -9.773 1.00 1.00HATOM 5459 H5*2 GB 9 -20.904 27.286 -10.243 1.00 1.00HATOM 5460 H4*GB 9 -20.493 27.668 -7.986 1.00 1.00HATOM 5461 H1*GB 9 -17.779 29.094 -6.784 1.00 1.00HATOM 5462 H2*1 GB 9 -18.114 30.826 -8.268 1.00 1.00HATOM 5463 H2*2 GB 9 -17.673 29.813 -9.697 1.00 1.00HATOM 5464 H3*GB 9 -20.015 29.601 -9.962 1.00 1.00HATOM 5465 H8GB 9 -16.314 27.961 -10.108 1.00 1.00HATOM 5466 H1GB 9 -12.110 28.116 -5.121 1.00 1.00HATOM 5467 H21 GB 9 -15.028 29.144 -3.313 1.00 1.00HATOM 5468 H22 GB 9 -13.284 28.700 -3.156 1.00 1.00HATOM 5469 P CB 10 -20.868 31.636 -8.095 1.00 1.00PATOM 5470 O1P CB 10 -22.094 31.996 -7.319 1.00 1.00OATOM 5471 O2P CB 10 -21.176 32.136 -9.466 1.00 1.00OATOM 5472 O5*CB 10 -19.589 32.264 -7.457 1.00 1.00OATOM 5473 C5*CB 10 -19.587 32.170 -6.031 1.00 1.00CATOM 5474 C4*CB 10 -18.234 32.618 -5.427 1.00 1.00CATOM 5475 O4*CB 10 -17.161 31.747 -5.882 1.00 1.00OATOM 5476 C1*CB 10 -15.928 32.412 -5.519 1.00 1.00CATOM 5477 C2*CB 10 -16.244 33.921 -5.479 1.00 1.00CATOM 5478 C3*CB 10 -17.758 34.026 -5.851 1.00 1.00CATOM 5479 O3*CB 10 -18.438 34.942 -5.015 1.00 1.00OATOM 5480 N1CB 10 -14.974 32.009 -6.543 1.00 1.00NATOM 5481 C6CB 10 -15.334 31.783 -7.832 1.00 1.00CATOM 5482 C5CB 10 -14.504 31.274 -8.746 1.00 1.00CATOM 5483 N4CB 10 -12.215 30.493 -9.197 1.00 1.00NATOM 5484 C4CB 10 -13.099 30.948 -8.353 1.00 1.00CATOM 5485 N3CB 10 -12.782 31.195 -7.157 1.00 1.00NATOM 5486 O2CB 10 -13.330 31.894 -5.025 1.00 1.00OATOM 5487 C2CB 10 -13.693 31.747 -6.183 1.00 1.00CATOM 5488 H5*1 CB 10 -19.750 31.127 -5.738 1.00 1.00HATOM 5489 H5*2 CB 10 -20.401 32.754 -5.639 1.00 1.00HATOM 5490 H4*CB 10 -18.231 32.619 -4.335 1.00 1.00HATOM 5491 H1*CB 10 -15.752 31.976 -4.493 1.00 1.00HATOM 5492 H2*1 CB 10 -16.119 34.314 -4.465 1.00 1.00HATOM 5493 H2*2 CB 10 -15.586 34.527 -6.168 1.00 1.00HATOM 5494 H3*CB 10 -17.962 34.301 -6.906 1.00 1.00HATOM 5495 H6CB 10 -16.315 32.055 -8.126 1.00 1.00HATOM 5496 H5CB 10 -14.816 31.091 -9.769 1.00 1.00HATOM 5497 H41 CB 10 -11.203 30.370 -8.919 1.00 1.00HATOM 5498 H42 CB 10 -12.493 30.353 -10.167 1.00 1.00HATOM 5499 P TB 11 -18.279 36.516 -5.075 1.00 1.00P
ATOM 5500 O1P TB 11 -19.363 37.115 -4.226 1.00 1.00OATOM 5501 O2P TB 11 -18.482 36.915 -6.493 1.00 1.00OATOM 5502 O5*TB 11 -16.793 36.910 -4.660 1.00 1.00OATOM 5503 C5*TB 11 -16.357 37.084 -3.309 1.00 1.00CATOM 5504 C4*TB 11 -14.832 37.055 -3.440 1.00 1.00CATOM 5505 O4*TB 11 -14.273 35.984 -4.219 1.00 1.00OATOM 5506 C1*TB 11 -12.956 36.338 -4.625 1.00 1.00CATOM 5507 C2*TB 11 -12.976 37.890 -4.772 1.00 1.00CATOM 5508 C3*TB 11 -14.291 38.381 -4.071 1.00 1.00CATOM 5509 O3*TB 11 -14.074 39.278 -2.958 1.00 1.00OATOM 5510 N1TB 11 -12.650 35.651 -5.866 1.00 1.00NATOM 5511 C6TB 11 -13.576 35.693 -6.870 1.00 1.00CATOM 5512 C5M TB 11 -14.499 35.102 -9.088 1.00 1.00CATOM 5513 C5TB 11 -13.418 35.051 -8.047 1.00 1.00CATOM 5514 O4TB 11 -11.879 33.791 -9.285 1.00 1.00OATOM 5515 C4TB 11 -12.126 34.332 -8.222 1.00 1.00CATOM 5516 N3TB 11 -11.277 34.282 -7.192 1.00 1.00NATOM 5517 O2TB 11 -10.662 34.801 -5.083 1.00 1.00OATOM 5518 C2TB 11 -11.476 34.922 -5.995 1.00 1.00CATOM 5519 H5*1 TB 11 -16.698 36.180 -2.794 1.00 1.00HATOM 5520 H5*2 TB 11 -16.792 37.930 -2.754 1.00 1.00HATOM 5521 H4*TB 11 -14.429 36.883 -2.427 1.00 1.00HATOM 5522 H1*TB 11 -12.277 36.042 -3.793 1.00 1.00HATOM 5523 H2*1 TB 11 -12.156 38.288 -4.177 1.00 1.00HATOM 5524 H2*2 TB 11 -12.967 38.234 -5.798 1.00 1.00HATOM 5525 H3*TB 11 -15.092 38.843 -4.705 1.00 1.00HATOM 5526 H6TB 11 -14.525 36.230 -6.847 1.00 1.00HATOM 5527 H51 TB 11 -14.117 35.443 -10.085 1.00 1.00HATOM 5528 H52 TB 11 -14.785 34.065 -9.271 1.00 1.00HATOM 5529 H53 TB 11 -15.415 35.686 -8.986 1.00 1.00HATOM 5530 H3TB 11 -10.496 33.752 -7.471 1.00 1.00HATOM 5531 P CB 12 -13.415 40.706 -2.886 1.00 1.00PATOM 5532 O1P CB 12 -13.642 41.103 -1.467 1.00 1.00OATOM 5533 O2P CB 12 -14.098 41.613 -3.866 1.00 1.00OATOM 5534 O5*CB 12 -11.843 40.616 -3.145 1.00 1.00OATOM 5535 C5*CB 12 -10.814 40.226 -2.254 1.00 1.00CATOM 5536 C4*CB 12 -9.53340.006 -3.032 1.00 1.00CATOM 5537 O4*CB 12 -9.82839.108 -4.120 1.00 1.00OATOM 5538 C1*CB 12 -8.79339.119 -5.112 1.00 1.00CATOM 5539 C2*CB 12 -8.52740.652 -5.180 1.00 1.00CATOM 5540 C3*CB 12 -9.04341.210 -3.828 1.00 1.00CATOM 5541 O3*CB 12 -8.02441.758 -3.056 1.00 1.00OATOM 5542 N1CB 12 -9.34038.646 -6.376 1.00 1.00NATOM 5543 C6CB 12 -10.544 39.083 -6.828 1.00 1.00CATOM 5544 C5CB 12 -11.132 38.633 -7.960 1.00 1.00CATOM 5545 N4CB 12 -10.987 37.086 -9.833 1.00 1.00NATOM 5546 C4CB 12 -10.507 37.585 -8.729 1.00 1.00CATOM 5547 N3CB 12 -9.35037.240 -8.359 1.00 1.00NATOM 5548 O2CB 12 -7.53237.374 -7.017 1.00 1.00OATOM 5549 C2CB 12 -8.70037.720 -7.139 1.00 1.00CATOM 5550 H5*1 CB 12 -11.151 39.385 -1.598 1.00 1.00HATOM 5551 H5*2 CB 12 -10.687 41.048 -1.556 1.00 1.00H
ATOM 5552 H4*CB 12 -8.752 39.564 -2.367 1.00 1.00HATOM 5553 H1*CB 12 -7.939 38.522 -4.753 1.00 1.00HATOM 5554 H2*1 CB 12 -7.496 40.835 -5.312 1.00 1.00HATOM 5555 H2*2 CB 12 -9.129 41.158 -5.971 1.00 1.00HATOM 5556 H3*CB 12 -9.932 41.872 -4.071 1.00 1.00HATOM 5557 H6 CB 12 -11.048 39.851 -6.222 1.00 1.00HATOM 5558 H5 CB 12 -12.083 39.029 -8.265 1.00 1.00HATOM 5559 H41CB 12 -10.412 36.479 -10.450 1.00 1.00HATOM 5560 H42CB 12 -11.906 37.388 -10.178 1.00 1.00HATOM 5561 P GB 13 -7.073 43.034 -3.229 1.00 1.00PATOM 5562 O1PGB 13 -6.297 43.476 -2.031 1.00 1.00OATOM 5563 O2PGB 13 -7.802 44.182 -3.858 1.00 1.00OATOM 5564 O5*GB 13 -5.904 42.576 -4.284 1.00 1.00OATOM 5565 C5*GB 13 -4.859 41.753 -3.818 1.00 1.00CATOM 5566 C4*GB 13 -3.974 41.438 -5.065 1.00 1.00CATOM 5567 O4*GB 13 -4.793 40.766 -6.057 1.00 1.00OATOM 5568 C1*GB 13 -4.535 41.391 -7.341 1.00 1.00CATOM 5569 C2*GB 13 -4.284 42.898 -6.955 1.00 1.00CATOM 5570 C3*GB 13 -3.412 42.750 -5.683 1.00 1.00CATOM 5571 O3*GB 13 -2.080 42.382 -6.130 1.00 1.00OATOM 5572 N9 GB 13 -5.677 41.168 -8.227 1.00 1.00NATOM 5573 C8 GB 13 -6.843 41.756 -8.064 1.00 1.00CATOM 5574 N7 GB 13 -7.637 41.377 -8.968 1.00 1.00NATOM 5575 C5 GB 13 -6.989 40.374 -9.757 1.00 1.00CATOM 5576 O6 GB 13 -8.544 39.475 -11.238 1.00 1.00OATOM 5577 C6 GB 13 -7.384 39.551 -10.884 1.00 1.00CATOM 5578 N1 GB 13 -6.342 38.812 -11.396 1.00 1.00NATOM 5579 N2 GB 13 -4.181 38.090 -11.521 1.00 1.00NATOM 5580 C2 GB 13 -5.060 38.825 -10.921 1.00 1.00CATOM 5581 N3 GB 13 -4.746 39.470 -9.877 1.00 1.00NATOM 5582 C4 GB 13 -5.770 40.320 -9.243 1.00 1.00CATOM 5583 H5*1 GB 13 -5.397 40.818 -3.475 1.00 1.00HATOM 5584 H5*2 GB 13 -4.170 42.094 -3.068 1.00 1.00HATOM 5585 H4*GB 13 -3.115 40.786 -4.876 1.00 1.00HATOM 5586 H1*GB 13 -3.729 40.852 -7.891 1.00 1.00HATOM 5587 H2*1 GB 13 -3.788 43.453 -7.719 1.00 1.00HATOM 5588 H2*2 GB 13 -5.234 43.527 -6.763 1.00 1.00HATOM 5589 H3*GB 13 -3.402 43.611 -5.019 1.00 1.00HATOM 5590 H8 GB 13 -7.186 42.491 -7.351 1.00 1.00HATOM 5591 H1 GB 13 -6.591 38.261 -12.223 1.00 1.00HATOM 5592 H21GB 13 -3.216 37.998 -11.125 1.00 1.00HATOM 5593 H22GB 13 -4.417 37.621 -12.389 1.00 1.00HATOM 5594 P AB 14 -0.974 43.331 -6.757 1.00 1.00PATOM 5595 O1PAB 140.147 43.235 -5.788 1.00 1.00OATOM 5596 O2PAB 14 -1.472 44.751 -6.655 1.00 1.00OATOM 5597 O5*AB 14 -0.623 42.891 -8.251 1.00 1.00OATOM 5598 C5*AB 140.267 41.766 -8.359 1.00 1.00CATOM 5599 C4*AB 140.314 41.376 -9.873 1.00 1.00CATOM 5600 O4*AB 14 -1.048 40.979 -10.210 1.00 1.00OATOM 5601 C1*AB 14 -1.349 41.351 -11.568 1.00 1.00CATOM 5602 C2*AB 14 -0.416 42.533 -11.868 1.00 1.00CATOM 5603 C3*AB 140.722 42.546 -10.835 1.00 1.00C
ATOM 5604 O3*AB 14 1.981 42.171 -11.453 1.00 1.00OATOM 5605 N9AB 14 -2.777 41.736 -11.686 1.00 1.00NATOM 5606 C8AB 14 -3.393 42.442 -10.799 1.00 1.00CATOM 5607 N7AB 14 -4.627 42.559 -11.041 1.00 1.00NATOM 5608 C5AB 14 -4.926 41.880 -12.201 1.00 1.00CATOM 5609 N6AB 14 -7.298 42.162 -12.605 1.00 1.00NATOM 5610 C6AB 14 -6.059 41.644 -12.950 1.00 1.00CATOM 5611 N1AB 14 -5.893 40.830 -14.024 1.00 1.00NATOM 5612 C2AB 14 -4.714 40.179 -14.298 1.00 1.00CATOM 5613 N3AB 14 -3.618 40.506 -13.598 1.00 1.00NATOM 5614 C4AB 14 -3.697 41.358 -12.585 1.00 1.00CATOM 5615 H5*1 AB 14 -0.070 40.993 -7.6691.00 1.00HATOM 5616 H5*2 AB 14 1.258 42.090 -8.0541.00 1.00HATOM 5617 H4*AB 14 1.017 40.523 -10.041 1.00 1.00HATOM 5618 H1*AB 14 -1.126 40.492 -12.184 1.00 1.00HATOM 5619 H2*1 AB 14 0.042 42.568 -12.867 1.00 1.00HATOM 5620 H2*2 AB 14 -0.979 43.504 -11.787 1.00 1.00HATOM 5621 H3*AB 14 0.770 43.486 -10.207 1.00 1.00HATOM 5622 H8AB 14 -2.827 42.787 -9.9701.00 1.00HATOM 5623 H61 AB 14 -7.406 42.643 -11.681 1.00 1.00HATOM 5624 H62 AB 14 -8.115 41.987 -13.191 1.00 1.00HATOM 5625 H2AB 14 -4.637 39.457 -15.074 1.00 1.00HATOM 5626 P AB 15 2.802 42.972 -12.572 1.00 1.00PATOM 5627 O1P AB 15 4.188 42.421 -12.603 1.00 1.00OATOM 5628 O2P AB 15 2.881 44.321 -12.020 1.00 1.00OATOM 5629 O5*AB 15 2.170 42.882 -14.040 1.00 1.00OATOM 5630 C5*AB 15 2.031 41.643 -14.749 1.00 1.00CATOM 5631 C4*AB 15 1.120 41.842 -15.968 1.00 1.00CATOM 5632 O4*AB 15 -0.159 42.194 -15.418 1.00 1.00OATOM 5633 C1*AB 15 -0.768 43.197 -16.209 1.00 1.00CATOM 5634 C2*AB 15 0.453 44.129 -16.425 1.00 1.00CATOM 5635 C3*AB 15 1.490 43.056 -16.860 1.00 1.00CATOM 5636 O3*AB 15 1.154 42.647 -18.183 1.90 1.00OATOM 5637 N9AB 15 -1.824 43.770 -15.348 1.00 1.00NATOM 5638 C8AB 15 -1.738 44.435 -14.218 1.00 1.00CATOM 5639 N7AB 15 -2.903 44.749 -13.791 1.00 1.00NATOM 5640 C5AB 15 -3.865 44.242 -14.573 1.00 1.00CATOM 5641 N6AB 15 -5.818 44.901 -13.515 1.00 1.00NATOM 5642 C6AB 15 -5.252 44.343 -14.589 1.00 1.00CATOM 5643 N1AB 15 -5.855 43.927 -15.707 1.00 1.00NATOM 5644 C2AB 15 -5.205 43.155 -16.606 1.00 1.00CATOM 5645 N3AB 15 -3.874 42.988 -16.576 1.00 1.00NATOM 5646 C4AB 15 -3.171 43.579 -15.600 1.00 1.00CATOM 5647 H5*1 AB 15 1.565 40.899 -14.050 1.00 1.00HATOM 5648 H5*2 AB 15 3.024 41.294 -15.047 1.00 1.00HATOM 5649 H4*AB 15 1.095 40.898 -16.542 1.00 1.00HATOM 5650 H1*AB 15 -1.184 42.882 -17.172 1.00 1.00HATOM 5651 H2*1 AB 15 0.327 44.839 -17.249 1.00 1.00HATOM 5652 H2*2 AB 15 0.758 44.690 -15.550 1.00 1.00HATOM 5653 H3*AB 15 2.535 43.337 -16.677 1.00 1.00HATOM 5654 H8AB 15 -0.821 44.738 -13.674 1.00 1.00HATOM 5655 H61 AB 15 -5.235 45.212 -12.697 1.00 1.00H
ATOM 5656 H62AB 15 -6.839 44.805 -13.371 1.00 1.00HATOM 5657 H2 AB 15 -5.818 42.644 -17.364 1.00 1.00HATOM 5658 H9 AB 151.328 43.353 -18.798 1.00 1.00HTERHETATM 5659 H5*1 DRG C 1 -6.234 4.404 -4.753 1.00 1.00HHETATM 5660 H5*2 DRG C 1 -7.640 5.215 -5.457 1.00 1.00HHETATM 5661 H4*DRG C 1 -5.518 6.203 -6.211 1.00 1.00HHETATM 5662 H1*DRG C 1 -4.682 9.088 -5.766 1.00 1.00HHETATM 5663 H2*1 DRG C 1 -3.036 7.500 -5.113 1.00 1.00HHETATM 5664 H2*2 DRG C 1 -3.432 7.765 -3.331 1.00 1.00HHETATM 5665 H3*DRG C 1 -4.886 5.962 -3.282 1.00 1.00HHETATM 5666 H8DRG C 1 -7.116 8.923 -3.087 1.00 1.00HHETATM 5667 H61 DRG C 1 -6.048 12.553 -0.414 1.00 1.00HHETATM 5668 H62 DRG C 1 -4.643 13.636 -0.176 1.00 1.00HHETATM 5669 H2DRG C 1 -1.642 12.255 -3.458 1.00 1.00HHETATM 5670 O1DRG C 1 -6.465 4.206 -1.473 1.00 1.00OHETATM 5671 H3DRG C 1 -3.408 5.274 -5.618 1.00 1.00HHETATM 5672 P DRG C 1 -7.712 4.826 -2.256 1.00 1.00PHETATM 5673 O1P DRG C 1 -8.592 5.594 -1.295 1.00 1.00OHETATM 5674 O2P DRG C 1 -8.561 3.811 -2.977 1.00 1.00OHETATM 5675 O5*DRG C 1 -7.262 5.761 -3.432 1.00 1.00OHETATM 5676 C5*DRG C 1 -6.840 5.335 -4.712 1.00 1.00CHETATM 5677 C4*DRG C 1 -5.821 6.420 -5.169 1.00 1.00CHETATM 5678 O4*DRG C 1 -6.218 7.779 -4.952 1.00 1.00OHETATM 5679 C1*DRG C 1 -4.947 8.538 -4.797 1.00 1.00CHETATM 5680 C2*DRG C 1 -3.853 7.586 -4.341 1.00 1.00CHETATM 5681 C3*DRG C 1 -4.533 6.224 -4.325 1.00 1.00CHETATM 5682 O3*DRG C 1 -3.692 5.130 -4.720 1.00 1.00OHETATM 5683 N9DRG C 1 -5.231 9.507 -3.766 1.00 1.00NHETATM 5684 C8DRG C 1 -6.272 9.528 -3.047 1.00 1.00CHETATM 5685 N7DRG C 1 -6.158 10.412 -2.154 1.00 1.00NHETATM 5686 C5DRG C 1 -5.018 11.103 -2.345 1.00 1.00CHETATM 5687 N6DRG C 1 -5.085 12.834 -0.637 1.00 1.00NHETATM 5688 C6DRG C 1 -4.479 12.217 -1.694 1.00 1.00CHETATM 5689 N1DRG C 1 -3.292 12.621 -2.168 1.00 1.00NHETATM 5690 C2DRG C 1 -2.646 11.967 -3.180 1.00 1.00CHETATM 5691 N3DRG C 1 -3.200 10.926 -3.832 1.00 1.00NHETATM 5692 C4DRG C 1 -4.378 10.496 -3.400 1.00 1.00CHETATM 5693 P12 DRG C 1 -5.757 2.877 -2.006 1.00 1.00PHETATM 5694 O12 DRG C 1 -6.628 2.525 -3.129 1.00 1.00OHETATM 5695 O13 DRG C 1 -4.368 2.965 -2.594 1.00 1.00OHETATM 5696 O14 DRG C 1 -5.954 1.686 -0.980 1.00 1.00OHETATM 5697 P12 DRG C 1 -7.421 1.164 -0.904 1.00 1.00PHETATM 5698 O12 DRG C 1 -7.795 0.2080.168 1.00 1.00OHETATM 5699 O13 DRG C 1 -8.524 2.044 -1.374 1.00 1.00OHETATM 5700 O14 DRG C 1 -7.878 0.803 -2.282 1.00 1.00OTERATOM 5701 P TD 1 -16.243 44.859 -18.466 1.00 1.00PATOM 5702 O1P TD 1 -15.981 46.317 -18.398 1.00 1.00OATOM 5703 O2P TD 1 -17.352 44.483 -19.420 1.00 1.00OATOM 5704 O5*TD 1 -14.832 44.218 -18.868 1.00 1.00OATOM 5705 C5*TD 1 -14.342 44.382 -20.210 1.00 1.00C
ATOM 5706 C4*TD 1 -12.864 43.864 -20.288 1.00 1.00 CATOM 5707 O4*TD 1 -12.002 44.648 -19.443 1.00 1.00 OATOM 5708 C1*TD 1 -10.766 43.887 -19.189 1.00 1.00 CATOM 5709 C2*TD 1 -11.059 42.405 -19.588 1.00 1.00 CATOM 5710 C3*TD 1 -12.609 42.444 -19.799 1.00 1.00 CATOM 5711 O3*TD 1 -13.085 41.480 -20.721 1.00 1.00 OATOM 5712 N1TD 1 -10.333 44.120 -17.843 1.00 1.00 NATOM 5713 C6TD 1 -11.192 44.693 -16.964 1.00 1.00 CATOM 5714 C5M TD 1 -11.609 45.628 -14.657 1.00 1.00 CATOM 5715 C5TD 1 -10.813 44.955 -15.700 1.00 1.00 CATOM 5716 O4TD 1 -9.026 44.806 -14.152 1.00 1.00 OATOM 5717 C4TD 1 -9.440 44.585 -15.281 1.00 1.00 CATOM 5718 N3TD 1 -8.643 43.979 -16.206 1.00 1.00 NATOM 5719 O2TD 1 -8.246 43.474 -18.290 1.00 1.00 OATOM 5720 C2TD 1 -9.069 43.818 -17.478 1.00 1.00 CATOM 5721 H5*1 TD 1 -14.331 45.478 -20.389 1.00 1.00 HATOM 5722 H5*2 TD 1 -15.053 43.979 -20.941 1.00 1.00 HATOM 5723 H4*TD 1 -12.472 43.952 -21.370 1.00 1.00 HATOM 5724 H1*TD 1 -9.908 44.287 -19.814 1.00 1.00 HATOM 5725 H2*1 TD 1 -10.558 42.206 -20.542 1.00 1.00 HATOM 5726 H2*2 TD 1 -10.661 41.605 -18.974 1.00 1.00 HATOM 5727 H3*TD 1 -13.066 42.351 -18.795 1.00 1.00 HATOM 5728 H6TD 1 -12.210 45.079 -17.201 1.00 1.00 HATOM 5729 H51 TD 1 -11.410 46.728 -14.678 1.00 1.00 HATOM 5730 H52 TD 1 -12.668 45.494 -14.745 1.00 1.00 HATOM 5731 H53 TD 1 -11.352 45.216 -13.697 1.00 1.00 HATOM 5732 H3TD 1 -7.705 43.640 -15.928 1.00 1.00 HATOM 5733 H10 TD 1 -16.450 44.625 -17.502 1.00 1.00 HATOM 5734 P TD 2 -13.141 39.897 -20.668 1.00 1.00 PATOM 5735 O1P TD 2 -13.867 39.327 -21.867 1.00 1.00 OATOM 5736 O2P TD 2 -13.779 39.372 -19.436 1.00 1.00 OATOM 5737 O5*TD 2 -11.632 39.399 -20.790 1.00 1.00 OATOM 5738 C5*TD 2 -10.592 39.382 -21.789 1.00 1.00 CATOM 5739 C4*TD 2 -9.268 38.934 -21.167 1.00 1.00 CATOM 5740 O4*TD 2 -8.991 39.812 -20.107 1.00 1.00 OATOM 5741 C1*TD 2 -8.246 39.047 -19.100 1.00 1.00 CATOM 5742 C2*TD 2 -8.761 37.545 -19.130 1.00 1.00 CATOM 5743 C3*TD 2 -9.363 37.500 -20.590 1.00 1.00 CATOM 5744 O3*TD 2 -8.718 36.581 -21.484 1.00 1.00 OATOM 5745 N1TD 2 -8.584 39.583 -17.816 1.00 1.00 NATOM 5746 C6TD 2 -9.946 39.723 -17.505 1.00 1.00 CATOM 5747 C5M TD 2 -11.751 40.621 -16.089 1.00 1.00 CATOM 5748 C5TD 2 -10.294 40.349 -16.375 1.00 1.00 CATOM 5749 O4TD 2 -9.635 41.444 -14.420 1.00 1.00 OATOM 5750 C4TD 2 -9.277 40.831 -15.423 1.00 1.00 CATOM 5751 N3TD 2 -7.989 40.616 -15.779 1.00 1.00 NATOM 5752 O2TD 2 -6.475 40.024 -17.274 1.00 1.00 OATOM 5753 C2TD 2 -7.666 40.078 -16.969 1.00 1.00 CATOM 5754 H5*1 TD 2 -10.389 40.377 -22.227 1.00 1.00 HATOM 5755 H5*2 TD 2 -10.896 38.692 -22.671 1.00 1.00 HATOM 5756 H4*TD 2 -8.408 38.930 -21.886 1.00 1.00 HATOM 5757 H1*TD 2 -7.209 39.123 -19.408 1.00 1.00 H
ATOM 5758 H2*1 TD 2 -7.82736.907 -18.990 1.00 1.00HATOM 5759 H2*2 TD 2 -9.48237.317 -18.346 1.00 1.00HATOM 5760 H3*TD 2 -10.401 37.123 -20.490 1.00 1.00HATOM 5761 H6 TD 2 -10.702 39.367 -18.213 1.00 1.00HATOM 5762 H51TD 2 -11.907 41.728 -15.904 1.00 1.00HATOM 5763 H52TD 2 -12.322 40.362 -17.012 1.00 1.00HATOM 5764 H53TD 2 -12.139 39.972 -15.256 1.00 1.00HATOM 5765 H3 TD 2 -7.28140.874 -15.170 1.00 1.00HATOM 5766 P CD 3 -8.44834.971 -21.337 1.00 1.00PATOM 5767 O1PCD 3 -7.67934.400 -22.490 1.00 1.00OATOM 5768 O2PCD 3 -9.78134.262 -21.219 1.00 1.00OATOM 5769 O5*CD 3 -7.43434.614 -20.122 1.00 1.00OATOM 5770 C5*CD 3 -6.02234.909 -20.312 1.00 1.00CATOM 5771 C4*CD 3 -5.32434.967 -18.928 1.00 1.00CATOM 5772 O4*CD 3 -5.90336.023 -18.087 1.00 1.00OATOM 5773 C1*CD 3 -5.54835.700 -16.772 1.00 1.00CATOM 5774 C2*CD 3 -5.67034.147 -16.741 1.00 1.00CATOM 5775 C3*CD 3 -5.53033.660 -18.198 1.00 1.00CATOM 5776 O3*CD 3 -4.39332.862 -18.477 1.00 1.00OATOM 5777 N1 CD 3 -6.59736.322 -15.965 1.00 1.00NATOM 5778 C6 CD 3 -7.93836.212 -16.241 1.00 1.00CATOM 5779 C5 CD 3 -8.86636.871 -15.557 1.00 1.00CATOM 5780 N4 CD 3 -9.36338.397 -13.748 1.00 1.00NATOM 5781 C4 CD 3 -8.44637.675 -14.377 1.00 1.00CATOM 5782 N3 CD 3 -7.24037.665 -14.024 1.00 1.00NATOM 5783 O2 CD 3 -5.12237.022 -14.336 1.00 1.00OATOM 5784 C2 CD 3 -6.26036.949 -14.794 1.00 1.00CATOM 5785 H5*1 CD 3 -6.06535.893 -20.778 1.00 1.00HATOM 5786 H5*2 CD 3 -5.50234.266 -20.980 1.00 1.00HATOM 5787 H4*CD 3 -4.19735.194 -19.014 1.00 1.00HATOM 5788 H1*CD 3 -4.50136.070 -16.502 1.00 1.00HATOM 5789 H2*1 CD 3 -4.83233.835 -16.143 1.00 1.00HATOM 5790 H2*2 CD 3 -6.58633.834 -16.247 1.00 1.00HATOM 5791 H3*CD 3 -6.50633.214 -18.523 1.00 1.00HATOM 5792 H6 CD 3 -8.23935.621 -17.104 1.00 1.00HATOM 5793 H5 CD 3 -9.87736.860 -15.869 1.00 1.00HATOM 5794 H41CD 3 -9.10638.950 -12.937 1.00 1.00HATOM 5795 H42CD 3 -10.331 38.394 -14.074 1.00 1.00HATOM 5796 P GD 4 -3.84531.501 -17.802 1.00 1.00PATOM 5797 O1PGD 4 -2.59531.040 -18.476 1.00 1.00OATOM 5798 O2PGD 4 -4.92230.498 -17.944 1.00 1.00OATOM 5799 O5*GD 4 -3.35131.774 -16.299 1.00 1.00OATOM 5800 C5*GD 4 -2.17532.555 -15.920 1.00 1.00CATOM 5801 C4*GD 4 -2.21932.938 -14.460 1.00 1.00CATOM 5802 O4*GD 4 -3.46333.619 -14.269 1.00 1.00OATOM 5803 C1*GD 4 -3.81133.531 -12.854 1.00 1.00CATOM 5804 C2*GD 4 -3.50432.096 -12.443 1.00 1.00CATOM 5805 C3*GD 4 -2.32731.764 -13.437 1.00 1.00CATOM 5806 O3*GD 4 -1.04231.561 -12.831 1.00 1.00OATOM 5807 N9 GD 4 -5.24833.785 -12.718 1.00 1.00NATOM 5808 C8 GD 4 -6.15033.270 -13.510 1.00 1.00CATOM 5809 N7 GD 4 -7.27733.714 -13.212 1.00 1.00N
ATOM 5810 C5 GD 4-7.131 34.630 -12.128 1.00 1.00CATOM 5811 O6 GD 4-9.213 35.446 -11.535 1.00 1.00OATOM 5812 C6 GD 4-8.000 35.489 -11.338 1.00 1.00CATOM 5813 N1 GD 4-7.412 36.205 -10.388 1.00 1.00NATOM 5814 N2 GD 4-5.600 36.721 -9.0571.00 1.00NATOM 5815 C2 GD 4-6.071 36.066 -10.094 1.00 1.00CATOM 5816 N3 GD 4-5.317 35.274 -10.745 1.00 1.00NATOM 5817 C4 GD 4-5.867 34.541 -11.849 1.00 1.00CATOM 5818 H5*1 GD 4-2.067 33.508 -16.507 1.00 1.00HATOM 5819 H5*2 GD 4-1.276 32.004 -16.217 1.00 1.00HATOM 5820 H4*GD 4-1.371 33.585 -14.200 1.00 1.00HATOM 5821 H1*GD 4-3.265 34.301 -12.232 1.00 1.00HATOM 5822 H2*1 GD 4-3.168 32.086 -11.421 1.00 1.00HATOM 5823 H2*2 GD 4-4.436 31.527 -12.517 1.00 1.00HATOM 5824 H3*GD 4-2.603 30.854 -13.926 1.00 1.00HATOM 5825 H8 GD 4-6.022 32.557 -14.353 1.00 1.00HATOM 5826 H1 GD 4-7.970 36.736 -9.8701.00 1.00HATOM 5827 H21GD 4-4.590 36.663 -8.8481.00 1.00HATOM 5828 H22GD 4-6.225 37.206 -8.3901.00 1.00HATOM 5829 P AD 5-0.638 30.399 -11.761 1.00 1.00PATOM 5830 O1PAD 5 0.865 30.376 -11.845 1.00 1.00OATOM 5831 O2PAD 5-1.276 29.073 -11.979 1.00 1.00OATOM 5832 O5*AD 5-1.042 30.957 -10.328 1.00 1.00OATOM 5833 C5*AD 5-0.461 32.189 -9.8051.00 1.00CATOM 5834 C4*AD 5-1.310 32.726 -8.6001.00 1.00CATOM 5835 O4*AD 5-2.631 32.989 -9.0081.00 1.00OATOM 5836 C1*AD 5-3.588 32.785 -7.9641.00 1.00CATOM 5837 C2*AD 5-3.011 31.503 -7.3171.00 1.00CATOM 5838 C3*AD 5-1.510 31.644 -7.5171.00 1.00CATOM 5839 O3*AD 5-0.711 32.149 -6.3641.00 1.00OATOM 5840 N9 AD 5-4.928 32.556 -8.4671.00 1.00NATOM 5841 C8 AD 5-5.210 31.756 -9.4421.00 1.00CATOM 5842 N7 AD 5-6.436 31.804 -9.7071.00 1.00NATOM 5843 C5 AD 5-7.059 32.694 -8.9331.00 1.00CATOM 5844 N6 AD 5-9.220 32.767 -9.8731.00 1.00NATOM 5845 C6 AD 5-8.357 33.186 -8.9121.00 1.00CATOM 5846 N1 AD 5-8.675 33.979 -7.8671.00 1.00NATOM 5847 C2 AD 5-7.758 34.249 -6.9071.00 1.00CATOM 5848 N3 AD 5-6.454 33.898 -7.0061.00 1.00NATOM 5849 C4 AD 5-6.088 33.148 -8.0551.00 1.00CATOM 5850 H5*1 AD 5-0.467 32.942 -10.606 1.00 1.00HATOM 5851 H5*2 AD 5 0.594 32.054 -9.4761.00 1.00HATOM 5852 H4*AD 5-0.880 33.689 -8.2331.00 1.00HATOM 5853 H1*AD 5-3.565 33.636 -7.2491.00 1.00HATOM 5854 H2*1 AD 5-3.226 31.457 -6.2721.00 1.00HATOM 5855 H2*2 AD 5-3.402 30.591 -7.7991.00 1.00HATOM 5856 H3*AD 5-1.097 30.643 -7.7341.00 1.00HATOM 5857 H8 AD 5-4.465 31.101 -9.9061.00 1.00HATOM 5858 H61AD 5-8.886 32.245 -10.707 1.00 1.00HATOM 5859 H62AD 5-10.173 33.081 -9.8321.00 1.00HATOM 5860 H2 AD 5-8.076 34.627 -5.9801.00 1.00HATOM 5861 P GD 6-0.501 31.223 -5.0771.00 1.00P
ATOM 5862 O1P GD 60.58531.922-4.3241.00 1.00OATOM 5863 O2P GD 6 -0.11329.894-5.5901.00 1.00OATOM 5864 O5*GD 6 -1.85431.175-4.2801.00 1.00OATOM 5865 C5*GD 6 -2.05632.043-3.1451.00 1.00CATOM 5866 C4*GD 6 -3.56431.854-2.6961.00 1.00CATOM 5867 O4*GD 6 -4.39831.933-3.9061.00 1.00OATOM 5868 C1*GD 6 -5.69331.373-3.5991.00 1.00CATOM 5869 C2*GD 65.38730.262-2.6011.00 1.00CATOM 5870 C3*GD 6 -3.89130.459-2.1631.00 1.00CATOM 5871 O3*GD 6 -3.63630.171-0.6971.00 1.00OATOM 5872 N9GD 6 -6.30930.833-4.8011.00 1.00NATOM 5873 C8GD 6 -5.70530.191-5.7131.00 1.00CATOM 5874 N7GD 6 -6.46229.981-6.6931.00 1.00NATOM 5875 C5GD 6 -7.76030.545-6.3531.00 1.00CATOM 5876 O6GD 6 -9.31830.204-8.0571.00 1.00OATOM 5877 C6GD 6 -9.09430.666-6.9471.00 1.00CATOM 5878 N1GD 6 -10.037 31.214-6.1161.00 1.00NATOM 5879 N2GD 6 -10.757 32.325-4.1711.00 1.00NATOM 5880 C2GD 6 -9.79131.753-4.8851.00 1.00CATOM 5881 N3GD 6 -8.60331.715-4.4291.00 1.00NATOM 5882 C4GD 6 -7.53831.050-5.1511.00 1.00CATOM 5883 H5*1 GD 6 -1.95733.089-3.4291.00 1.00HATOM 5884 H5*2 GD 6 -1.42431.804-2.2591.00 1.00HATOM 5885 H4*GD 6 -3.78932.688-1.9711.00 1.00HATOM 5886 H1*GD 6 -6.30232.186-3.1631.00 1.00HATOM 5887 H2*1 GD 6 -6.07930.438-1.7181.00 1.00HATOM 5888 H2*2 GD 6 -5.56029.235-2.9291.00 1.00HATOM 5889 H3*GD 6 -3.22229.761-2.6891.00 1.00HATOM 5890 H8GD 6 -4.66529.856-5.5071.00 1.00HATOM 5891 H1GD 6 -11.000 31.250-6.5051.00 1.00HATOM 5892 H21 GD 6 -10.535 32.744-3.2841.00 1.00HATOM 5893 H22 GD 6 -11.698 32.358-4.5981.00 1.00HATOM 5894 P CD 7 -4.08928.730-0.1281.00 1.00PATOM 5895 O1P CD 7 -3.46728.470 1.1881.00 1.00OATOM 5896 O2P CD 7 -3.68927.651-1.0821.00 1.00OATOM 5897 O5*CD 7 -5.65228.568 0.1821.00 1.00OATOM 5898 C5*CD 7 -6.39329.034 1.3441.00 1.00CATOM 5899 C4*CD 7 -7.96229.050 1.2041.00 1.00CATOM 5900 O4*CD 7 -8.31929.915 0.0831.00 1.00OATOM 5901 C1*CD 7 -9.55729.417-0.4951.00 1.00CATOM 5902 C2*CD 7 -9.87628.134 0.2741.00 1.00CATOM 5903 C3*CD 7 -8.51727.671 0.9231.00 1.00CATOM 5904 O3*CD 7 -8.64426.677 1.9521.00 1.00OATOM 5905 N1CD 7 -9.44229.021-1.9041.00 1.00NATOM 5906 C6CD 7 -8.28928.552-2.4361.00 1.00CATOM 5907 C5CD 7 -8.17728.153-3.6851.00 1.00CATOM 5908 N4CD 7 -9.19127.831-5.8481.00 1.00NATOM 5909 C4CD 7 -9.30528.172-4.6241.00 1.00CATOM 5910 N3CD 7 -10.452 28.557-4.1241.00 1.00NATOM 5911 O2CD 7 -11.681 29.094-2.3241.00 1.00OATOM 5912 C2CD 7 -10.548 28.951-2.7571.00 1.00CATOM 5913 H5*1 CD 7 -6.07430.078 1.4741.00 1.00H
ATOM 5914 H5*2 CD 7-6.040 28.514 2.2661.001.00HATOM 5915 H4*CD 7-8.543 29.542 2.0741.001.00HATOM 5916 H1*CD 7-10.26330.245-0.3401.001.00HATOM 5917 H2*1 CD 7-10.56528.330 1.1031.001.00HATOM 5918 H2*2 CD 7-10.36627.333-0.3661.001.00HATOM 5919 H3*CD 7-7.942 27.164 0.1781.001.00HATOM 5920 H6 CD 7-7.416 28.456-1.7541.001.00HATOM 5921 H5 CD 7-7.307 27.713-4.0831.001.00HATOM 5922 H41CD 7-9.972 27.886-6.4701.001.00HATOM 5923 H42CD 7-8.286 27.480-6.1401.001.00HATOM 5924 P GD 8-9.568 26.635 3.2001.001.00PATOM 5925 O1PGD 8-9.692 28.018 3.7251.001.00OATOM 5926 O2PGD 8-9.135 25.590 4.1971.001.00OATOM 5927 O5*GD 8-10.92126.231 2.4931.001.00OATOM 5928 C5*GD 8-12.25826.666 2.8131.001.00CATOM 5929 C4*GD 8-13.19026.239 1.6691.001.00CATOM 5930 O4*GD 8-12.58226.458 0.3911.001.00OATOM 5931 C1*GD 8-12.06225.178-0.1331.001.00CATOM 5932 C2*GD 8-13.23424.273 0.2921.001.00CATOM 5933 C3*GD 8-13.41524.686 1.7941.001.00CATOM 5934 O3*GD 8-14.78324.321 2.1411.001.00OATOM 5935 N9 GD 8-11.53625.186-1.5051.001.00NATOM 5936 C8 GD 8-10.22525.235-1.7691.001.00CATOM 5937 N7 GD 8-10.01125.198-2.9871.001.00NATOM 5938 C5 GD 8-11.30825.042-3.6721.001.00CATOM 5939 O6 GD 8-10.95224.971-6.0081.001.00OATOM 5940 C6 GD 8-11.75724.943-5.0431.001.00CATOM 5941 N1 GD 8-13.08624.742-5.2351.001.00NATOM 5942 N2 GD 8-15.20424.472-4.3391.001.00NATOM 5943 C2 GD 8-13.95024.736-4.1311.001.00CATOM 5944 N3 GD 8-13.54224.931-2.9171.001.00NATOM 5945 C4 GD 8-12.14625.066-2.6521.001.00CATOM 5946 H5*1 GD 8-12.31027.777 2.8301.001.00HATOM 5947 H5*2 GD 8-12.52126.310 3.8261.001.00HATOM 5948 H4*GD 8-14.15526.812 1.7421.001.00HATOM 5949 H1*GD 8-11.25424.839 0.4411.001.00HATOM 5950 H2*1 GD 8-14.15424.430-0.3261.001.00HATOM 5951 H2*2 GD 8-12.90623.235 0.1731.001.00HATOM 5952 H3*GD 8-12.70724.199 2.4351.001.00HATOM 5953 H8 GD 8-9.457 25.270-0.9971.001.00HATOM 5954 H1 GD 8-13.34724.549-6.1721.001.00HATOM 5955 H21GD 8-15.90824.447-3.5791.001.00HATOM 5956 H22GD 8-15.54924.219-5.2941.001.00HATOM 5957 P CD 9-15.05322.849 2.8181.001.00PATOM 5958 O1PCD 9-14.25521.814 2.1011.001.00OATOM 5959 O2PCD 9-14.81322.707 4.2721.001.00OATOM 5960 O5*CD 9-16.61722.548 2.6511.001.00OATOM 5961 C5*CD 9-17.23722.870 1.4121.001.00CATOM 5962 C4*CD 9-16.58022.260 0.1781.001.00CATOM 5963 O4*CD 9-16.94722.838-1.1571.001.00OATOM 5964 C1*CD 9-16.60621.891-2.1661.001.00CATOM 5965 C2*CD 9-17.18320.631-1.4181.001.00C
ATOM 5966 C3*CD 9-16.702 20.7010.036 1.00 1.00 CATOM 5967 O3*CD 9-17.607 20.0210.911 1.00 1.00 OATOM 5968 N1CD 9-15.239 21.765 -2.737 1.00 1.00 NATOM 5969 C6CD 9-14.138 21.654 -1.946 1.00 1.00 CATOM 5970 C5CD 9-12.946 21.724 -2.530 1.00 1.00 CATOM 5971 N4CD 9-11.517 22.087 -4.433 1.00 1.00 NATOM 5972 C4CD 9-12.691 21.942 -3.916 1.00 1.00 CATOM 5973 N3CD 9-13.763 21.891 -4.642 1.00 1.00 NATOM 5974 O2CD 9-16.019 21.853 -4.875 1.00 1.00 OATOM 5975 C2CD 9-15.089 21.781 -4.072 1.00 1.00 CATOM 5976 H5*1 CD 9-17.284 23.9341.216 1.00 1.00 HATOM 5977 H5*2 CD 9-18.288 22.6151.382 1.00 1.00 HATOM 5978 H4*CD 9-15.559 22.6640.145 1.00 1.00 HATOM 5979 H1*CD 9-17.346 21.933 -2.961 1.00 1.00 HATOM 5980 H2*1 CD 9-18.248 20.664 -1.382 1.00 1.00 HATOM 5981 H2*2 CD 9-16.950 19.727 -1.913 1.00 1.00 HATOM 5982 H3*CD 9-15.677 20.3030.247 1.00 1.00 HATOM 5983 H6CD 9-14.037 21.495 -0.871 1.00 1.00 HATOM 5984 H5CD 9-12.014 21.625 -1.914 1.00 1.00 HATOM 5985 H41 CD 9-11.405 22.255 -5.455 1.00 1.00 HATOM 5986 H42 CD 9-10.697 21.958 -3.804 1.00 1.00 HATOM 5987 P CD 10 -17.498 18.4230.975 1.00 1.00 PATOM 5988 O1P CD 10 -18.258 17.7792.068 1.00 1.00 OATOM 5989 O2P CD 10 -16.209 18.2751.701 1.00 1.00 OATOM 5990 O5*CD 10 -17.474 17.680 -0.436 1.00 1.00 OATOM 5991 C5*CD 10 -18.648 17.405 -1.205 1.00 1.00 CATOM 5992 C4*CD 10 -18.255 16.860 -2.583 1.00 1.00 CATOM 5993 O4*CD 10 -17.581 17.887 -3.352 1.00 1.00 OATOM 5994 C1*CD 10 -16.671 17.195 -4.300 1.00 1.00 CATOM 5995 C2*CD 10 -16.917 15.672 -3.994 1.00 1.00 CATOM 5996 C3*CD 10 -17.342 15.612 -2.542 1.00 1.00 CATOM 5997 O3*CD 10 -18.058 14.441 -2.227 1.00 1.00 OATOM 5998 N1CD 10 -15.316 17.633 -4.129 1.00 1.00 NATOM 5999 C6CD 10 -14.853 17.945 -2.906 1.00 1.00 CATOM 6000 C5CD 10 -13.599 18.351 -2.744 1.00 1.00 CATOM 6001 N4CD 10 -11.430 18.804 -3.750 1.00 1.00 NATOM 6002 C4CD 10 -12.671 18.387 -3.869 1.00 1.00 CATOM 6003 N3CD 10 -13.092 18.023 -4.992 1.00 1.00 NATOM 6004 O2CD 10 -14.761 17.356 -6.302 1.00 1.00 OATOM 6005 C2CD 10 -14.461 17.630 -5.138 1.00 1.00 CATOM 6006 H5*1 CD 10 -19.258 18.283 -1.313 1.00 1.00 HATOM 6007 H5*2 CD 10 -19.255 16.626 -0.744 1.00 1.00 HATOM 6008 H4*CD 10 -19.159 16.636 -3.115 1.00 1.00 HATOM 6009 H1*CD 10 -16.965 17.412 -5.309 1.00 1.00 HATOM 6010 H2*1 CD 10 -17.775 15.367 -4.585 1.00 1.00 HATOM 6011 H2*2 CD 10 -16.004 15.085 -4.295 1.00 1.00 HATOM 6012 H3*CD 10 -16.475 15.656 -1.893 1.00 1.00 HATOM 6013 H6CD 10 -15.479 17.869 -2.006 1.00 1.00 HATOM 6014 H5CD 10 -13.112 18.633 -1.752 1.00 1.00 HATOM 6015 H41 CD 10 -10.777 18.733 -4.580 1.00 1.00 HATOM 6016 H42 CD 10 -11.042 19.096 -2.828 1.00 1.00 HATOM 6017 P GD 11 -17.342 13.006 -2.163 1.00 1.00 P
ATOM 6018 O1P GD 11 -16.496 13.027-0.907 1.00 1.00 OATOM 6019 O2P GD 11 -18.397 11.953-2.074 1.00 1.00 OATOM 6020 O5*GD 11 -16.404 12.786-3.421 1.00 1.00 OATOM 6021 C5*GD 11 -16.969 12.312-4.704 1.00 1.00 CATOM 6022 C4*GD 11 -15.888 12.053-5.821 1.00 1.00 CATOM 6023 O4*GD 11 -15.143 13.165-6.222 1.00 1.00 OATOM 6024 C1*GD 11 -13.890 12.708-6.638 1.00 1.00 CATOM 6025 C2*GD 11 -13.905 11.164-6.407 1.00 1.00 CATOM 6026 C3*GD 11 -14.949 10.960-5.378 1.00 1.00 CATOM 6027 O3*GD 11 -15.741 9.762 -5.361 1.00 1.00 OATOM 6028 N9GD 11 -12.932 13.417-5.795 1.00 1.00 NATOM 6029 C8GD 11 -13.106 13.851-4.547 1.00 1.00 CATOM 6030 N7GD 11 -12.068 14.428-4.123 1.00 1.00 NATOM 6031 C5GD 11 -11.042 14.387-5.163 1.00 1.00 CATOM 6032 O6GD 11 -9.082 15.500-4.573 1.00 1.00 OATOM 6033 C6GD 11 -9.652 14.837-5.422 1.00 1.00 CATOM 6034 N1GD 11 -9.098 14.449-6.570 1.00 1.00 NATOM 6035 N2GD 11 -9.123 13.453-8.574 1.00 1.00 NATOM 6036 C2GD 11 -9.790 13.767-7.512 1.00 1.00 CATOM 6037 N3GD 11 -11.008 13.414-7.350 1.00 1.00 NATOM 6038 C4GD 11 -11.702 13.695-6.123 1.00 1.00 CATOM 6039 H5*1 GD 11 -17.672 13.025-5.112 1.00 1.00 HATOM 6040 H5*2 GD 11 -17.533 11.367-4.445 1.00 1.00 HATOM 6041 H4*GD 11 -16.389 11.746-6.714 1.00 1.00 HATOM 6042 H1*GD 11 -13.760 12.876-7.706 1.00 1.00 HATOM 6043 H2*1 GD 11 -14.203 10.672-7.391 1.00 1.00 HATOM 6044 H2*2 GD 11 -12.907 10.870-6.070 1.00 1.00 HATOM 6045 H3*GD 11 -14.654 11.258-4.383 1.00 1.00 HATOM 6046 H8GD 11 -14.004 13.823-3.965 1.00 1.00 HATOM 6047 H1GD 11 -8.131 14.794-6.720 1.00 1.00 HATOM 6048 H21 GD 11 -9.585 12.905-9.261 1.00 1.00 HATOM 6049 H22 GD 11 -8.150 13.722-8.725 1.00 1.00 HATOM 6050 P GD 12 -15.163 8.312 -5.126 1.00 1.00 PATOM 6051 O1P GD 12 -15.735 7.446 -6.208 1.00 1.00 OATOM 6052 O2P GD 12 -15.593 7.702 -3.827 1.00 1.00 OATOM 6053 O5*GD 12 -13.587 8.250 -5.257 1.00 1.00 OATOM 6054 C5*GD 12 -13.099 7.659 -6.443 1.00 1.00 CATOM 6055 C4*GD 12 -11.527 7.698 -6.443 1.00 1.00 CATOM 6056 O4*GD 12 -11.057 9.072 -6.557 1.00 1.00 OATOM 6057 C1*GD 12 -9.716 9.150 -6.104 1.00 1.00 CATOM 6058 C2*GD 12 -9.446 7.793 -5.431 1.00 1.00 CATOM 6059 C3*GD 12 -10.813 7.163 -5.160 1.00 1.00 CATOM 6060 O3*GD 12 -10.865 5.753 -4.931 1.00 1.00 OATOM 6061 N9GD 12 -9.502 10.296-5.215 1.00 1.00 NATOM 6062 C8GD 12 -10.333 10.699-4.320 1.00 1.00 CATOM 6063 N7GD 12 -9.912 11.691-3.691 1.00 1.00 NATOM 6064 C5GD 12 -8.618 12.015-4.172 1.00 1.00 CATOM 6065 O6GD 12 -7.654 13.784-2.998 1.00 1.00 OATOM 6066 C6GD 12 -7.543 12.976-3.890 1.00 1.00 CATOM 6067 N1GD 12 -6.420 12.966-4.673 1.00 1.00 NATOM 6068 N2GD 12 -5.287 12.039-6.388 1.00 1.00 NATOM 6069 C2GD 12 -6.329 11.999-5.670 1.00 1.00 C
ATOM 6070 N3GD12 -7.24211.106 -5.899 1.00 1.00NATOM 6071 C4GD12 -8.47611.143 -5.151 1.00 1.00CATOM 6072 H5*1 GD12 -13.372 8.291-7.312 1.00 1.00HATOM 6073 H5*2 GD12 -13.460 6.618-6.601 1.00 1.00HATOM 6074 H4*GD12 -11.141 7.182-7.315 1.00 1.00HATOM 6075 H1*GD12 -9.0579.337-6.984 1.00 1.00HATOM 6076 H2*1 GD12 -8.8487.131-6.094 1.00 1.00HATOM 6077 H2*2 GD12 -8.8317.933-4.505 1.00 1.00HATOM 6078 H3*GD12 -11.236 7.777-4.335 1.00 1.00HATOM 6079 H8GD12 -11.295 10.174 -4.089 1.00 1.00HATOM 6080 H1GD12 -5.62813.545 -4.457 1.00 1.00HATOM 6081 H21 GD12 -5.22911.417 -7.174 1.00 1.00HATOM 6082 H22 GD12 -4.50112.670 -6.257 1.00 1.00HATOM 6083 H11 GD12 -10.197 5.671-4.205 1.00 1.00HTERHETATM 6084 MG1 MG E 1-10.966 4.075-5.574 1.00 1.00MGTERHETATM 6085 MG1 MG F 1-8.3252.204-3.133 1.00 1.00MGTERHETATM 6086 X X G 1-2.975 -10.873 -2.518 1.00 1.00XTERHETATM 6087 X X H 1-23.388 -6.544-22.744 1.00 1.00XTERHETATM 6088 X X I 1 6.776 -5.202 11.238 1.00 1.00XCONECT 5659 5676CONECT 5660 5676CONECT 5661 5677CONECT 5662 5679CONECT 5663 5680CONECT 5664 5680CONECT 5665 5681CONECT 5666 5684CONECT 5667 5687CONECT 5668 5687CONECT 5669 5690CONECT 5670 5672 5693CONECT 5671 5682CONECT 5672 5670 5673 5674 5675CONECT 5673 5672CONECT 5674 5672CONECT 5675 5672 5676CONECT 5676 5660 5659 5675 5677CONECT 5677 5661 5676 5678 5681CONECT 5678 5677 5679CONECT 5679 5662 5678 5680 5683CONECT 5680 5679 5664 5663 5681CONECT 5681 5680 5665 5677 5682CONECT 5682 5681 5671CONECT 5683 5679 5684 5692CONECT 5684 5683 5666 5685CONECT 5685 5684 5686CONECT 5686 5685 5688 5692
CONECT 5687 5668 5667 5688CONECT 5688 5687 5686 5689CONECT 5689 5688 5690CONECT 5690 5669 5689 5691CONECT 5691 5690 5692CONECT 5692 5683 5686 5691CONECT 5693 5670 5694 5695 5696CONECT 5694 5693CONECT 5695 5693CONECT 5696 5693 5697CONECT 5697 5696 5698 5699 5700CONECT 5698 5697CONECT 5699 5697CONECT 5700 5697END本領(lǐng)域技術(shù)人員將認(rèn)識(shí)到除了特定所述的那些在此所述的本發(fā)明易于改變和改進(jìn)。應(yīng)當(dāng)理解本發(fā)明包括所有這樣的改變和改進(jìn)。本發(fā)明還單獨(dú)地或共同地包括該說(shuō)明書(shū)中涉及的或表明的所有步驟、特征、組合物和化合物，以及任何兩個(gè)或多個(gè)所述步驟或特征的任意和全部組合。
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序列表<110>MELBOURNE HEALTH(outside of US)BARTHOLOMEUSZ，Angeline(US Only)TEHAN，Ben(US Only)CHALMERS，David(US Only)KUIPER，Mike(US Only)<120>病毒聚合酶及其調(diào)節(jié)<130>12458670/EJH<150>AU 2003902983<151>2003-06-13<160>18<170>PatentIn version 3.1<210>1<211>373<212>PRT<213>人工序列<220>
<223>ADV抗性HBV聚合酶的氨基酸序列<400>1Asn Ser Lys Pro Cys Ser Asp Tyr Cys Leu Ser His Ile Val Asn Leu1 5 10 15Leu Glu Asp Trp Gly Pro Cys Ala Glu His Gly Glu His His Ile Arg20 25 30
Ile Pro Arg Thr Pro Ala Arg Val Thr Gly Gly Val Phe Leu Val Asp35 40 45Lys Asn Pro His Asn Thr Ala Glu Ser Arg Leu Val Val Asp Phe Ser50 55 60Gln Phe Ser Arg Gly Asn Tyr Arg Val Ser Trp Pro Lys Phe Ala Val65 70 75 80Pro Asn Leu Gln Ser Leu Thr Asn Leu Leu Ser Ser Asn Leu Ser Trp85 90 95Leu Ser Leu Asp Val Ser Ala Ala Phe Tyr His Leu Pro Leu His Pro100 105 110Ala Ala Met Pro His Leu Leu Val Gly Ser Ser Gly Leu Ser Arg Tyr115 120 125Val Ala Arg Leu Ser Ser Asn Ser Arg Ile Phe Asn Tyr Gln His Gly130 135 140Thr Met Gln Asn Leu His Asp Ser Cys Ser Arg Asn Leu Tyr Val Ser145 150 155 160Leu Leu Leu Leu Tyr Gln Thr Phe Gly Arg Lys Leu His Leu Tyr Ser165 170 175His Pro Ile Ile Leu Gly Phe Arg Lys Ile Pro Met Gly Val Gly Leu180 185 190Ser Pro Phe Leu Leu Ala Gln Phe Thr Ser Ala Ile Cys Ser Val Val195 200 205Arg Arg Ala Phe Pro His Cys Leu Ala Phe Ser Tyr Met Asp Asp Val210 215 220Val Leu Gly Ala Lys Ser Val Gln His Leu Glu Ser Leu Phe Thr Ala225 230 235 240Val Thr Asn Phe Leu Leu Ser Leu Gly Ile His Leu Asn Pro Asn Lys245 250 255
Thr Lys Arg Trp Gly Tyr Ser Leu His Phe Met Gly Tyr Val Ile Gly260 265 270Cys Tyr Gly Ser Leu Pro Gln Asp His Ile Ile Gln Lys Ile Lys Glu275 280 285Cys Phe Arg Lys Leu Pro Val Asn Arg Pro Ile Asp Trp Lys Val Cys290 295 300Gln Arg Ile Val Gly Leu Leu Gly Phe Ala Ala Pro Phe Thr Gln Cys305 310 315 320Gly Tyr Pro Ala Leu Met Pro Leu Tyr Ala Cys Ile Gln Ser Lys Gln325 330 335Ala Phe Thr Phe Ser Pro Thr Tyr Lys Ala Phe Leu Cys Lys Gln Tyr340 345 350Leu Asn Leu Tyr Pro Val Ala Arg Gln Arg Pro Gly Leu Cys Gln Val355 360 365Phe Ala Asp Ala Thr370<210>2<211>12<212>PRT<213>人工序列<220>
<223>HBV基序1的氨基酸序列<400>2Gly Gly Val Phe Leu Val Asp Lys Asn Pro His Asn1 5 10<210>3<211>12<212>PRT
<213>人工序列<220>
<223>WHV基序1的氨基酸序列<400>3Gly Gly Val Phe Leu Val Asp Lys Asn Pro Asn Asn1 5 10<210>4<211>12<212>PRT<213>人工序列<220>
<223>DHBV基序1的氨基酸序列<400>4Gly Arg Leu Phe Leu Val Asp Lys Asn Ser Arg Asn1 5 10<210>5<211>10<212>PRT<213>人工序列<220>
<223>HIV基序1的氨基酸序列<400>5Thr Pro Val Phe Ala Ile Lys Lys Lys Asp1 5 10<210>6<211>11
<212>PRT<213>人工序列<220>
<223>HBV基序2的氨基酸序列<400>6Thr Thr Glu Ser Arg Leu Val Val Asp Phe Ser1 5 10<210>7<211>11<212>PRT<213>人工序列<220>
<223>WHV基序2的氨基酸序列<400>7Ser Ser Glu Ser Arg Leu Val Val Asp Phe Ser1 5 10<210>8<21l>11<212>PRT<213>人工序列<220>
<223>DHBV基序2的氨基酸序列<400>8Thr Thr Glu Ala Arg Leu Val Val Asp Phe Ser1 5 10<210>9
<211>11<212>PRT<213>人工序列<220>
<223>HIV基序2的氨基酸序列<400>9Ser Thr Lys Trp Arg Lys Leu Val Asp Phe Arg1 5 10<210>10<211>11<212>PRT<213>人工序列<220>
<223>PV基序2的氨基酸序列<400>10Gln Gly Lys Ser Arg Leu Ile Glu Ala Ser Ser1 5 10<210>11<211>12<212>PRT<213>人工序列<220>
<223>HCV基序2的氨基酸序列<400>11Gly Arg Lys Pro Ala Arg Leu Ile Val Phe Pro Asp1 5 10
<210>12<211>12<212>PRT<213>人工序列<220>
<223>DEN基序2的氨基酸序列<400>12Arg Ala Lys Gly Ser Arg Ala Ile Trp Tyr Met Trp1 5 10<210>13<211>12<212>PRT<213>人工序列<220>
<223>BVDV基序2的氨基酸序列<400>13Val Glu Lys Arg Pro Arg Val Ile Gln Tyr Pro Glu1 5 10<210>14<211>12<212>PRT<213>人工序列<220>
<223>Sindbis基序2的氨基酸序列<400>14His Thr Glu Glu Arg Pro Lys Val Gln Val Ile Gln1 5 10
<210>15<211>12<212>PRT<213>人工序列<220>
<223>HBV基序2的氨基酸序列<400>15Pro Gln Lys Ser Leu Asp His Ser Trp Trp Thr Ser1 5 10<210>16<211>10<212>PRT<213>人工序列<220>
<223>WHV基序2的氨基酸序列<400>16Ala Gln Asn Leu Asp Trp Trp Trp Thr Ser1 5 10<210>17<211>10<212>PRT<213>人工序列<220>
<223>DHBV基序2的氨基酸序列<400>17
Leu Arg Arg Leu Asp Trp Trp Trp Ile Ser1 5 10<210>18<211>373<212>PRT<213>人工序列<220>
<223>顯示核苷和核苷酸類似物的初級(jí)和次級(jí)突變性結(jié)合位點(diǎn)的氨基酸序列<400>18Asn Ser Lys Pro Cys Ser Asp Tyr Cys Leu Ser His Ile Val Asn Leu1 5 10 15Leu Glu Asp Trp Gly Pro Cys Ala Glu His Gly Glu His His Ile Arg20 25 30Ile Pro Arg Thr Pro Ala Arg Val Thr Gly Gly Val Phe Leu Val Asp35 40 45Lys Asn Pro His Asn Thr Ala Glu Ser Arg Leu Val Val Asp Phe Ser50 55 60Gln Phe Ser Arg Gly Asn Tyr Arg Val Ser Trp Pro Lys Phe Ala Val65 70 75 80Pro Asn Leu Gln Ser Leu Thr Asn Leu Leu Ser Ser Asn Leu Ser Trp85 90 95Leu Ser Leu Asp Val Ser Ala Ala Phe Tyr His Leu Pro Leu His Pro100 105 110Ala Ala Met Pro His Leu Leu Val Gly Ser Ser Gly Leu Ser Arg Tyr115 120 125Val Ala Arg Leu Ser Ser Ash Ser Arg Ile Phe Asn Tyr Gln His Gly130 135 140Thr Met Gln Asn Leu His Asp Ser Cys Ser Arg Asn Leu Tyr Val Ser
145 150 155 160Leu Leu Leu Leu Tyr Gln Thr Phe Gly Arg Lys Leu His Leu Tyr Ser165 170 175His Pro Ile Ile Leu Gly Phe Arg Lys Ile Pro Met Gly Val Gly Leu180 185 190Ser Pro Phe Leu Leu Ala Gln Phe Thr Ser Ala Ile Cys Ser Val Val195 200 205Arg Arg Ala Phe Pro His Cys Leu Ala Phe Ser Tyr Met Asp Asp Val210 215 220Val Leu Gly Ala Lys Ser Val Gln His Leu Glu Ser Leu Phe Thr Ala225 230 235 240Val Thr Asn Phe Leu Leu Ser Leu Gly Ile His Leu Asn Pro Asn Lys245 250 255Thr Lys Arg Trp Gly Tyr Ser Leu His Phe Met Gly Tyr Val Ile Gly260 265 270Cys Tyr Gly Ser Leu Pro Gln Asp His Ile Ile Gln Lys Ile Lys Glu275 280 285Cys Phe Arg Lys Leu Pro Val Asn Arg Pro Ile Asp Trp Lys Val Cys290 295 300Gln Arg Ile Val Gly Leu Leu Gly Phe Ala Ala Pro Phe Thr Gln Cys305 310 315 320Gly Tyr Pro Ala Leu Met Pro Leu Tyr Ala Cys Ile Gln Ser Lys Gln325 330 335Ala Phe Thr Phe Ser Pro Thr Tyr Lys Ala Phe Leu Cys Lys Gln Tyr340 345 350Leu Asn Leu Tyr Pro Val Ala Arg Gln Arg Pro Gly Leu Cys Gln Val355 360 365Phe Ala Asp Ala Thr370
權(quán)利要求
1.HBV聚合酶逆轉(zhuǎn)錄酶(rt)結(jié)構(gòu)域原子坐標(biāo)的數(shù)據(jù)集，其中所述原子坐標(biāo)如表6中所列的。
2.權(quán)利要求1的數(shù)據(jù)集，其中對(duì)核苷或核苷酸類似物呈現(xiàn)抗性或降低敏感性的變體HBV聚合酶作圖對(duì)應(yīng)于rt結(jié)構(gòu)域的氨基酸殘基位置編號(hào)28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和/或245-257。
3.權(quán)利要求1或2的數(shù)據(jù)集，其中對(duì)核苷或核苷酸類似物呈現(xiàn)抗性或降低敏感性的變體HBV聚合酶作圖對(duì)應(yīng)于rt結(jié)構(gòu)域的氨基酸殘基位置編號(hào)4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266。
4.權(quán)利要求1或2或3的數(shù)據(jù)集，其中對(duì)核苷或核苷酸類似物呈現(xiàn)抗性或降低敏感性的變體HBV聚合酶包括選自以下位置的突變r(jià)tA21，rtA38，rtY54，rtN76，rtL91，rtF122，rtY124，rtT128，rtQ130，rtT184，rtM204，rtS202，rtH248，rtY252，rtS21，rtN/S/T/I/V53，rtY54，rtS57，rtL91，rtS116，rtL122，rtF122，rtN124，rtY124 rtH126，rtY126，rtT128N，rtP130，rtD131，rtV134，rtY135，rtY141，rtL145，rtF151，rtL180，rtA181，rtS202，rtI204，rtK212，rtL217，rtS219，rtI235，rtN236，rtN238，sP120，sM125，sS126，sT127，sT118，sM133，sM133，sF134，sS143，sD144，sG145，sW172，sI195，sS207，sY225，間隔基L97，間隔基K115，間隔基H116，間隔基L128，間隔基S137，間隔基R139，間隔基F142，rtA97，rtH126，rtS135，rtM204，PreS1 N114，PreS1 T115，PreS2 F22，PreS2 V39，PreS2 P52，sL89，sT118，sF161，sE164，sI195，sI208，PreS1 E86，PreS1 N91，PreS2 P41，sQ30，sP120，sL176，sV194，rtS21，rtL122，rtN124，rtH126，rtP130，rtD131，rtY135，rtN/S/T/I/V53，rtY126，rtS202，rtI204，rfI235，sM125，sT127，sT118，sM133，sF134，sI195，sS207，sY225，rtG172，rtG174，rtP177，rtL180，rtT184，sR160，sE164，sF170，sL175，sQ181，sC/W182，sW196，sW196，sW196，sM198，sW199，sS204，sY206，sS210，sS210，sL216，sY255，rtL77，rtL77，rtL80，rtL80，rtH90，rtS117，rt125，rt128，rtQ125，rtQ125，rtY126Q，rtL128，rtT128，rtL132，rtN134，rtS137，rtN139，rtN139，rtY141，rtV/G142，rtL147，rtK149，rtG153，rtR153，rtW153，rtW153，rtF166，rtI169，rtF178，rtI187，rtI87，rtV191，rt191，rtN202，rtS202，rtS202，rtS213，rtV/G214，rtS219，rtS219，rtN/Q238，rtN/S/H238，rtN/S/H/T238，rtR242，rtR42，rtN248，rtI253，s118-207，s117-120，sI68，sC69，sL109，sG112，sS17，sT118，sK122，sT123，sT126，sT131，sN131，sM133，sM133，sY/F134，sC139，sK141，sD144，sG145，rtT128，rtL82，rtT135，rtT150，rtV163，rtT184，rtA00，rtF202，rtS213，rtQ215，rtS219，rtA22，rtI224，rtL229，rtL235，rtN238，rtS78，rt116DEL122，rtI163，rtL180，rtE8，rtV23，rtD31，rtY53，rtV58，rtA/S21，rtV/I/N/S/T53，rtV/I/N/S/T53，rtS/T/N/H/A54，PreS2 L11，PreS2 R17，DEL PreS2 18-21，PreS2 T30，PreS2 N54，sT13，PreS2 Q1，PreS2 Q1，rtH90，rtL/F108，rtL157，rtA181，rtV207，rtP109，rtN/H/A/S/Q238，s181，sP214，sF83，sL173，sW199，sI126，sK160，sS174，sA84，sS210，sC69，sC76，si110，sY134或sW172。
5.權(quán)利要求4的數(shù)據(jù)集，其中突變選自rtA21S，rtA38E，rtY54H，rtN76D，rtL91I，rtF122L，rtY124H，rtT128N，rtQ130P，rtT184G，rtM204V/I，rtS202I，rtH248N，rtY252L，rtS21A，rtN/S/T/I/V53D，rtY54H，rtS57P，rtL91I，rtS116P，rtL122F，rtF122L，rtN124H，rtY124H，rtH126R，rtY126Q，rtT128N，rtP130Q，rtD131N，rtV134D，rtY135C，rtY141Y/F，rtL145M，rtF151T/F，rtL180M，rtA181T，rtS202G，rtI204V，rtK212R，rtL217R，rtS219A，rtI235I/M，rtN236T，rtN238D，sP120T，sM125T，sS126T，sT127A，sT118R，sM133L/M，sM133T，sF134V，sS143S/T，sD144A，sG145A，sW172Stop，sI195M，sS207R，sY225Y/C，間隔基L97I，間隔基K115R，間隔基H116L，間隔基L128F，間隔基S137G，間隔基R139G，間隔基F142S，rtA97V，rtH126R，rtS135Y，rtM204I，PreS 1N114D，PreS 1T115S，PreS2 F22L，PreS2 V39A，PreS2 P52L，sL89V，sT118A，sF161L，sE164D，sI195M，sI208T，PreS1 E86Q，PreS1 N91K，PreS2 P41H，sQ30K，sP120T，sL176V，sV194F，rtS21A，rtL122F，rtN124H，rtH126R，rtP130Q，rtD131N，rtY135C，rtN/S/T/I/V53D，rtY126Q，rtS202G，rtI204V，rtI235I/M，sM125T，sT127A，sT118R，sM133T，sF134V，sI195M，sS207R，sY225Y/C，rtG172E，rtG174C，rtP177L，rtL180V，rtT184S，sR160N，sE164D，sF170L，sL175L/S，sQ181E/G/Q，sC/W182Y/STOP，sW196L，sW196S，sW196STOP，sM198I，sW199S，sS204T，sY206N，sS210K，sS210R，sL216STOP，sY255F，rtL77L/F，rtL77L/M/V，rtL80I，rtL80V，rtH90N/H，rtS117S/Y，rt125DELrt128，rtQ125K，rtQ125N，rtY126Q，rtL128L/M，rtT128A，rtL132L/M，rtN134G，rtS137T，rtN139H，rtN139K，rtY141Y/STOP，rtV/G142L，rtL147L/W，rtK149R，rtG153E，rtR153Q，rtW153S，rtW153Q，rtF166L，rtI169L，rtF178F/L，rtI187L，rtI187I/V，rtV191I，rtV191V/I，rtN202S，rtS202S/C，rtS202G，rtS213T，rtV/G214E，rtS219A，rtS219P，rtN/Q238H，rtN/S/H238N/K，rtN/S/H/T238/T/A/S/L，rtR242R/K，rtR242R/S，rtN248H，rtI253A，s118-207，s117-120DEL，sI68I/M，sC69F/L，sL109I/L，sG112R，sS17T，sT118R，sK122R，sT123P，sT126S，sT131N，sN131T，sM133K/M，sM133I，sY/F134S，sC139C/G，sK141E，sD144E，sG145R，rtT128T/I，rtL82M，rtT135C，rtT150A，rtV163I，rtT184S，rtA200V，rtF202V，rtS213T，rtQ215H，rtS219A，rtA222T，rtI224S，rtL229M，rtL235I，rtN238S，rtS78T，rt116DEL122，rtI163V，rtL180V，rtE8A，rtV23I，rtD31D/G，rtY53D，rtV58V/I，rtA/S21T，rtV/I/N/S/T53D，rtV/I/N/S/T53Y，rtS/T/N/H/A54Y/H，PreS2 L11L/A，PreS2 R17I，DELPreS2 18-21，PreS2 T30A，PreS2 N54H，sT13T/A，PreS2 Q1V，PreS2 Q1M，rtH90D，rtL/F108L，rtL157L/M，rtA181V，rtV207I，rtP109S，rtN/H/A/S/Q238K，s181M，sP214Q，sF83S，sL173F，sW199L，sI126T，sK160R，sS174N，sA84V，sS210N，sC69STOP/C，sC76Y，si110V/I，sY134N，sW172STOP/W，K32M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；N33D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；P34S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；H35I/L/D/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；T37W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P59S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；K60M/F/P/S/T/W/Y/C/A/R/N/D/C/Q/E/G/H/I/L/缺失；F61P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；A62R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；V63A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；D83C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/缺失；V84A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；S85T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；A86R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/Y/W/YV/缺失；Y89V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺矢；H90I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；I/L91K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/缺失；P177S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；F178P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；L179K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；L180K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；A181R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Q183E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；F183P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；T184W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；Y203V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；M204F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；L235K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N236D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；T237W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P237S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；B238D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H238I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；A238R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；S239T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；Q238E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；K239M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；L247K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N248D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H248I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；F249P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；M250F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；G251H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/缺失；和V251A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失。
6.權(quán)利要求2至5任一項(xiàng)的數(shù)據(jù)集，其中核苷或核苷酸類似物選自ADV、LMV、FCV、FTC、ETV、DAPD、TDF和/或DXG。
7.使用編程的計(jì)算機(jī)來(lái)鑒定藥劑的計(jì)算機(jī)輔助方法，該藥劑可能能夠結(jié)合HBV聚合酶的結(jié)構(gòu)域并任選地調(diào)節(jié)至少一種HBV聚合酶的功能活性，包括預(yù)測(cè)對(duì)藥劑的抗病毒反應(yīng)，該方法包括步驟(a)將包括HBV聚合酶原子坐標(biāo)的數(shù)據(jù)輸入編程的計(jì)算機(jī)中，該聚合酶具有選自氨基酸殘基28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257，或4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266區(qū)域內(nèi)的突變，如但不限于；rtA21S，rtA38E，rtY54H，rtN76D，rtL91I，rtF122L，rtY124H，rtT128N，rtQ130P，rtT184G，rtM204V/I，rtS202I，rtH248N，rtY252L，rtS21A，rtN/S/T/I/V53D，rtY54H，rtS57P，rtL91I，rtS116P，rtL122F，rtF122L，rtN124H，rtY124H，rtH126R，rtY126Q，rtT128N，rtP130Q，rtD131N，rtV134D，rtY135C，rtY141Y/F，rtL145M，rtF151T/F，rtL180M，rtA181T，rtS202G，rtI204V，rtK212R，rtL217R，rtS219A，rtI235I/M，rtN236T，rtN238D，sP120T，sM125T，sS126T，sT127A，sT118R，sM133L/M，sM133T，sF134V，sS143S/T，sD144A，sG145A，sW172Stop，sI195M，sS207R，sY225Y/C，間隔基L97I，間隔基K115R，間隔基H116L，間隔基L128F，間隔基S137G，間隔基R139G，間隔基F142S，rtA97V，rtH126R，rtS135Y，rtM204I，PreS1 N114D，PreS1T115S，PreS2 F22L，PreS2 V39A，PreS2 P52L，sL89V，sT118A，sF161L，sE164D，sI195M，sI208T，PreS1 E86Q，PreS1 N91K，PreS2P41H，sQ30K，sP120T，sL176V，sV194F，rtS21A，rtL122F，rtN124H，rtH126R，rtP130Q，rtD131N，rtY135C，rtN/S/T/I/V53D，rtY126Q，rtS202G，rtI204V，rtI235I/M，sM125T，sT127A，sT118R，sM133T，sF134V，sI195M，sS207R，sY225Y/C，rtG172E，rtG174C，rtP177L，rtL180V，rtT184S，sR160N，sE164D，sF170L，sL175L/S，sQ181E/G/Q，sC/W182Y/STOP，sW196L，sW196S，sW196STOP，sM198I，sW199S，sS204T，sY206N，sS210K，sS210R，sL216STOP，sY255F，rtL77L/F，rtL77L/M/V，rtL80I，rtL80V，rtH90N/H，rtS117S/Y，rt125DELrt128，rtQ125K，rtQ125N，rtY126Q，rtL128L/M，rtT128A，rtL132L/M，rtN134G，rtS137T，rtN139H，rtN139K，rtY141Y/STOP，rtV/G142L，rtL147L/W，rtK149R，rtG153E，rtR153Q，rtW153S，rtW153Q，rtF166L，rtI169L，rtF178F/L，rtI187L，rtI187I/V，rtV191I，rtV191V/I，rtN202S，rtS202S/C，rtS202G，rtS213T，rtV/G214E，rtS219A，rtS219P，rtN/Q238H，rtN/S/H238N/K，rtN/S/H/T238/T/A/S/L，rt242R/K，rtR242R/S，rtN248H，rtI253A，s118-207，s117-120DEL，sI68I/M，sC69F/L，sL109I/L，sG112R，sS17T，sT118R，sK122R，sT123P，sT126S，sT131N，sN131T，sM133K/M，sM133I，sY/F134S，sC139C/G，sK141E，sD144E，sG145R，rtT128T/I，rtL82M，rtT135C，rtT150A，rtV163I，rtT184S，rtA200V，rtF202V，rtS213T，rtQ215H，rtS219A，rtA222T，rtI224S，rtL229M，rtL235I，rtN238S，rtS78T，rt116DEL122，rtI163V，rtL180V，rtE8A，rtV23I，rtD31D/G，rtY53D，rtV58V/I，rtA/S21T，rtV/I/N/S/T53D，rtV/I/N/S/T53Y，rtS/T/N/H/A54Y/H，PreS2 L11L/A，PreS2R17I，DEL PreS2 18-21，PreS2 T30A，PreS2 N54H，sT13T/A，PreS2 Q1V，PreS2 Q1M，rtH90D，rtL/F108L，rtL157L/M，rtA181V，rtV207I，rtP109S，rtN/H/A/S/Q238K，s181M，sP214Q，sF83S，sL173F，sW199L，sI126T，sK160R，sS174N，sA84V，sS210N，sC69STOP/C，sC76Y，si110V/I，sY134N，sW172STOP/W，K32M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；N33D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；P34S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；H35I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；T37W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P59S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；K60M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；F61P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；A62R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；V63A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；D83C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/缺失；V84A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；S85T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；A86R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/YV/缺失；Y89V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；H90I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；I/L91K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/缺失；P177S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；F178P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；L179K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；L180K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；A181R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Q183E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；F183P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；T184W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；Y203V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；M204F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；L235K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N236D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；T237W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P237S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；N238D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H238I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；A238R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；S239T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；Q238E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；K239M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；L247K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N248D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H248I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；F249P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；M25QF/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；G251H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/缺失；和V251A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；(b)使用計(jì)算機(jī)方法，產(chǎn)生與(a)中限定的原子坐標(biāo)具有立體化學(xué)互補(bǔ)性結(jié)構(gòu)的一套原子坐標(biāo)或其子集，由此產(chǎn)生標(biāo)準(zhǔn)數(shù)據(jù)集；(c)使用處理器，將標(biāo)準(zhǔn)數(shù)據(jù)集包括于化學(xué)結(jié)構(gòu)的計(jì)算機(jī)數(shù)據(jù)庫(kù)；(d)使用計(jì)算機(jī)方法，從數(shù)據(jù)庫(kù)中選擇與所述標(biāo)準(zhǔn)數(shù)據(jù)集的部分相似的化學(xué)結(jié)構(gòu)；和(e)輸出所選擇的與標(biāo)準(zhǔn)數(shù)據(jù)集的部分相似的化學(xué)結(jié)構(gòu)。
8.權(quán)利要求7的計(jì)算機(jī)輔助方法，進(jìn)一步包括獲得具有步驟(d)和(e)中所選化學(xué)結(jié)構(gòu)的藥劑并測(cè)試化合物調(diào)節(jié)至少一種HBV聚合酶功能活性的能力的步驟。
9.用于產(chǎn)生分子或分子復(fù)合物三維圖像的計(jì)算機(jī)或其軟件部分，其包括分子或分子混合物同系物的三維圖像，其中同系物包括氨基酸主鏈原子的標(biāo)準(zhǔn)差不大于1.5_的結(jié)構(gòu)域，其中計(jì)算機(jī)包括(a)機(jī)器可讀數(shù)據(jù)存儲(chǔ)器介質(zhì)，包括用機(jī)器可讀數(shù)據(jù)編碼的數(shù)據(jù)存儲(chǔ)材料，其中數(shù)據(jù)包括HBV聚合酶的結(jié)構(gòu)坐標(biāo)，該聚合酶具有選自氨基酸殘基28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257，或4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266區(qū)域內(nèi)的突變，如但不限于rtA21S，rtA38E，rtY54H，rtN76D，rtL91I，rtF122L，rtY124H，rtT128N，rtQ130P，rtT184G，rtM204V/I，rtS202I，rtH248N，rtY252L，rtS21A，rtN/S/T/I/V53D，rtY54H，rtS57P，rtL91I，rtS 116P，rtL122F，rtF122L，rtN124H，rtY124H，rtH126R，rtY126Q，rtT128N，rtP130Q，rtD131N，rtV134D，rtY135C，rtY141Y/F，rtL145M，rtF151T/F，rtL180M，rtA181T，rtS202G，rtI204V，rtK212R，rtL217R，rtS219A，rtI235I/M，rtN236T，rtN238D，sP120T，sM125T，sS126T，sT127A，sT118R，sM133L/M，sM133T，sF134V，sS143S/T，sD144A，sG145A，sW172Stop，sI195M，sS207R，sY225Y/C，間隔基L97I，間隔基K115R，間隔基H116L，間隔基L128F，間隔基S137G，間隔基R139G，間隔基F142S，rtA97V，rtH126R，rtS135Y，rtM204I，PreS1 N114D，PreS1 T115S，PreS2 F22L，PreS2 V39A，PreS2 P52L，sL89V，sT118A，sF161L，sE164D，sI195M，sI208T，PreS 1E86Q，PreS 1N91K，PreS2 P41H，sQ30K，sP120T，sL176V，sV194F，rtS21A，rtL122F，rtN124H，rtH126R，rtP130Q，rtD131N，rtY135C，rtN/S/T/I/V53D，rtY126Q，rtS202G，rtI204V，rtI235I/M，sM125T，sT127A，sT118R，sM133T，sF134V，sI195M，sS207R，sY225Y/C，rtG172E，rtG174C，rtP177L，rtL180V，rtT184S，sR160N，sE164D，sF170L，sL175L/S，sQ181E/G/Q，sC/W182Y/STOP，sW196L sW196S，sW196STOP，sM198I，sW199S，sS204T，sY206N，sS210K，sS210R，sL216STOP，sY255F，rtL77L/F，rtL77L/M/V，rtL80I，rtL80V，rtH90N/H，rtS117S/Y，rt125DELrt128，rtQ125K，rtQ125N，rtY126Q，rtL128L/M，rtT128A，rtL132L/M，rtN134G，rtS137T，rtN139H，rtN139K，rtY141Y/STOP，rtV/G142L，rtL147L/W，rtK149R，rtG153E，rtR153Q，rtW153S，rtW153Q，rtF166L，rtI169L，rtF178F/L，rtI187L，rtI187I/V，rtV191I，rtV191V/I，rtN202S，rtS202S/C，rtS202G，rtS213T，rtV/G214E，rtS219A，rtS219P，rtN/Q238H，rtN/S/H238N/K，rtN/S/H/T238/T/A/S/L，rtR242R/K，rtR242R/S，rtN248H，rtI253A，s118-207，s117-120DEL，sI68I/M，sC69F/L，sL109I/L，sG112R，sS17T，sT118R，sK122R，sT123P，sT126S，sT131N，sN131T，sM133K/M，sM133I，sY/F134S，sC139C/G，sK141E，sD144E，sG145R，rtT128T/I，rtL82M，rtT135C，rtT150A，rtV163I，rtT184S，rtA200V，rtF202V，rtS213T，rtQ215H，rtS219A，rtA222T，rtI224S，rtL229M，rtL235I，rtN238S，rtS78T，rt116DEL122，rtI163V，rtL180V，rtE8A，rtV23I，rtD31D/G，rtY53D，rtV58V/I，rtA/S21T，rtV/I/N/S/T53D，rtV/I/N/S/T53Y，rtS/T/N/H/A54Y/H，PreS2 L11L/A，PreS2 R17I，DELPreS2 18-21，PreS2 T30A，PreS2 N54H，sT13T/A，PreS2 Q1V，PreS2Q1M，rtH90D，rtL/F108L rtL157L/M，rtA181V，rtV207I，rtP109S，rtN/H/A/S/Q238K，s181M，sP214Q，sF83S，sL173F，sW199L，sI126T，sK160R，sS174N，sA84V，sS210N，sC69STOP/C，sC76Y，si110V/I，sY134N，sW172STOP/W，K32M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；N33D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；P34S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；H35I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；T37W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P59S/T/W/Y/N/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；K60M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；F61P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；A62R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；V63A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；D83C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/缺失；V84A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；S85T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；A86R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/YV/缺失；Y89V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；H90I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；I/L91K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/缺失；P177S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；F178P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；L179K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；L180K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；A181R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Q183E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；F183P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；T184W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；Y203V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；M204F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；L235K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N236D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；T237W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P237S/T/W/Y/C/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；N238D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H238I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；A238R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；S239T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；Q238E/G/H/I/L/K/M/F/P/S/R/W/Y/V/A/R/N/D/C/缺失；K239M/F/P/S/T/W/Y/C/A/R/N/D/C/Q/E/G/H/I/L/缺失；L247K/M/F/P/S/T/W/Y/V//A/R/N/D/C/Q/E/G/H/I/缺失；N248D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H248I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；F249P/S/T/W/Y/V/A/R/N/D/C/Q//E/G/H/I/L/K/M/缺失；M250F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；G251H/I/L/K/M/F/P/S/R/W/Y/V/A/R/N/D/C/Q/E/缺失；和V251A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；(b)存儲(chǔ)處理機(jī)器可讀數(shù)據(jù)指令的工作存儲(chǔ)器；(c)連接于工作存儲(chǔ)單元和機(jī)器可讀數(shù)據(jù)存儲(chǔ)介質(zhì)的中央處理單元，用于將機(jī)器可讀數(shù)據(jù)處理成三維圖像；和(d)連接于中央處理單元的顯示器，用于顯示三維結(jié)構(gòu)圖像。
10.計(jì)算機(jī)或其軟件部分，用于測(cè)定對(duì)應(yīng)于包括HBV聚合酶分子或分子復(fù)合物的三維結(jié)構(gòu)的至少部分結(jié)構(gòu)坐標(biāo)，其中計(jì)算機(jī)包括(a)機(jī)器可讀數(shù)據(jù)存儲(chǔ)介質(zhì)，包括用機(jī)器可讀數(shù)據(jù)編碼的數(shù)據(jù)存儲(chǔ)材料，其中數(shù)據(jù)包括至少部分HBV聚合酶的結(jié)構(gòu)坐標(biāo)，該聚合酶具有選自氨基酸殘基28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257，或4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266區(qū)域內(nèi)的突變，如但不限于rt21S，rtA38E，rtY54H，rtN76D，rtL91I，rtF122L，rtY124H，rtT128N，rtQ130P，rtT184G，rtM204V/I，rtS202I，rtH248N，rtY252L，rtS21A，rtN/S/T/I/V53D，rtY54H，rtS57P，rtL91I，rtS116P，rtL122F，rtF122L，rtN124H，rtY124H，rtH126R，rtY126Q，rtT128N，rtP130Q，rtD131N，rtV134D，rtY135C，rtY141Y/F，rtL145M，rtF151T/F，rtL180M，rtA181T，rtS202G，rt204V，rtK212R，rtL217R，rtS219A，rtI235I/M，rtN236T，rtN238D，sP120T，sM125T，sS126T，sT127A，sT118R，sM133L/M，sM133T，sF134V，sS143S/T，sD144A，sG145A，sW172Stop，sI195M，sS207R，sY225Y/C，間隔基L97I，間隔基K115R，間隔基H116L，間隔基L128F，間隔基S137G，間隔基R139G，間隔基F142S，rtA97V，rtH126R，rtS135Y，rtM204I，PreS1 N114D，PreS1 T115S，PreS2 F22L，PreS2 V39A，PreS2 P52L，sL89V，sT118A，sF161L，sE164D，sI195M，sI208T，PreS1 E86Q，PreS1 N91K，PreS2 P41H，sQ30K，sP120T，sL176V，sV194F，rtS21A，rtL122F，rtN124H，rtH126R，rtP130Q，rtD131N，rtY135C，rtN/S/T/I/V53D，rtY126Q，rtS202G，rtI204V，rtI235I/M，sM125T，sT127A，sT118R，sM133T，sF134V，sI195M，sS207R，sY225Y/C，rtG172E，rtG174C，rtP177L，rtL180V，rtT184S，sR160N，sE164D，sF170L，sL175L/S，sQ181E/G/Q，sC/W182Y/STOP，sW196L，sW196S，sW196STOP，sM198I，sW199S，sS204T，sY206N，sS210K，sS210R，sL216STOP，sY255F，rtL77L/F，rtL77L/M/V，rtL80I，rtL80V，rtH9N/H，rtS117S/Y，rt125DELrt128，rtQ125K，rtQ125N，rrY126Q，rtL128L/M，rtT128A，rtL132L/M，rtN134G，rtS137T，rtN139H，rtN139K，rtY141Y/STOP，rtV/G142L，rtL147L/W，rtK149R，rtG153E，rtR153Q，rtW153S，rtW153Q，rtF166L，rtI169L，rtF178F/L，rtI187L，rtI187I/V，rtV191I，rtV191V/I，rtN202S，rtS202S/C，rtS202G，rtS213T，rtV/G214E，rtS219A，rtS219P，rtN/Q238H，rtN/S/H238N/K，rtN/S/H/T238/T/A/S/L，rtR242R/K，rtR242R/S，rtN248H，rtI253A，s118-207，s117-120DEL，sI68I/M，sC69F/L，sL109I/L，sG112R，sS17T，sT118R，sK122R，sT123P，sT126S，sT131N，sN131T，sM133K/M，sM133I，sY/F134S，sC139C/G，sK141E，sD144E，sG145R，rtT128T/I，rtL82M，rtT135C，rtT150A，rtV163I，rtT184S，rtA200V，rtF202V，rtS213T，rtQ215H，rtS219A，rtA222T，rtI224S，rtL229M，rtL235I，rtN238S，rtS78T，rt116DEL122，rtI163V，rtL180V，rtE8A，rtV23I，rtD31D/G，rtY53D，rtV58V/I，rtA/S21T，rtV/I/N/S/T53D，rtV/I/N/S/T53Y，rtS/T/N/H/A54Y/H，PreS2 L11L/A，PreS2 R17I，DEL PreS2 18-21，PreS2 T30A，PreS2 N54H，sT13T/A，PreS2 Q1V，PreS2 Q1M，rtH90D，rtL/F108L，rtL157L/M，rtA181V，rtV207I，rtP109S，rtN/H/A/S/Q238K，s181M，sP214Q，sF83S，sL173F，sW199L，sI126T，sK160R，sS174N，sA84V，sS210N，sC69STOP/C，sC76Y，si110V/I，sY134N，sW172STOP/W，K32M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；N33D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；P34S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；H35I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；T37W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P59S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；K60M/F/P/S/T/W/Y/C/A/R/N/D/C/Q/E/G/H/I/L/缺失；F61P/S/T/W/Y/C/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；A62R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；V63A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；D83C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/缺失；V84A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；S85T/W/Y/C/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；A86R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Y89V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；H90I/L/K/M/F/P/S/T/W/Y/C/A/R/N/D/C/Q/E/G/缺失；I/L91K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/缺失；P177S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；F178P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；L179K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；L180K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；A181R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Q183E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；F183P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；T184W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；Y203V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；M204F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；L235K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N236D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；T237W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P237S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；N238D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H238I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；A238R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；S239T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；Q238E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；K239M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；L247K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N248D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H248I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；F249P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；M250F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；G251H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/缺失；和V251A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；(b)機(jī)器可讀數(shù)據(jù)存儲(chǔ)介質(zhì)，包括用機(jī)器可讀數(shù)據(jù)編碼的數(shù)據(jù)存儲(chǔ)材料，其中數(shù)據(jù)包括分子或分子復(fù)合物的原子坐標(biāo)；(c)工作存儲(chǔ)器，用于存儲(chǔ)處理(a)和(b)的機(jī)器可讀數(shù)據(jù)的指令；(d)連接于工作存儲(chǔ)器和(a)和(b)的機(jī)器可讀數(shù)據(jù)存儲(chǔ)介質(zhì)的中央處理單元，用于進(jìn)行(a)的機(jī)器可讀數(shù)據(jù)的轉(zhuǎn)換和用于將(b)的機(jī)器可讀數(shù)據(jù)處理成結(jié)構(gòu)坐標(biāo)；和(e)連接于中央處理單元的顯示器，用于顯示分子或分子復(fù)合物的結(jié)構(gòu)坐標(biāo)。
11.使用編程的計(jì)算機(jī)來(lái)鑒定藥劑的計(jì)算機(jī)輔助方法，該藥劑潛在能夠結(jié)合HBV聚合酶的結(jié)構(gòu)域并任選地調(diào)節(jié)至少一種HBV聚合酶的功能活性，包括預(yù)測(cè)對(duì)藥劑的抗病毒反應(yīng)，包括步驟(a)將數(shù)據(jù)輸入編程的計(jì)算機(jī)中，數(shù)據(jù)包括HBV聚合酶或其片段在位置28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257，和/或位置編號(hào)4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266的原子坐標(biāo)；(b)使用計(jì)算機(jī)方法，產(chǎn)生與(a)中限定的原子坐標(biāo)具有立體化學(xué)互補(bǔ)性結(jié)構(gòu)的一套原子坐標(biāo)或其子集，由此產(chǎn)生標(biāo)準(zhǔn)數(shù)據(jù)集；(c)使用處理器，將標(biāo)準(zhǔn)數(shù)據(jù)集包括于化學(xué)結(jié)構(gòu)的計(jì)算機(jī)數(shù)據(jù)庫(kù)；(d)使用計(jì)算機(jī)方法，從數(shù)據(jù)庫(kù)中選擇與所述標(biāo)準(zhǔn)數(shù)據(jù)集的部分相似的化學(xué)結(jié)構(gòu)；和(e)輸出所選擇的與標(biāo)準(zhǔn)數(shù)據(jù)集的部分相似的化學(xué)結(jié)構(gòu)。
12.通過(guò)權(quán)利要求7至11任一項(xiàng)方法鑒定的藥劑，其能夠與HBV聚合酶相互作用。
13.權(quán)利要求12的藥劑，其中該藥劑抑制或降低HBV聚合酶的活性。
14.權(quán)利要求13的藥劑，其中HBV聚合酶來(lái)自野生型HBV。
15.權(quán)利要求13的藥劑，其中HBV聚合酶來(lái)自對(duì)核苷或核苷酸類似物抗性或呈現(xiàn)降低敏感度的變體HBV。
16.權(quán)利要求15的藥劑，其中核苷或核苷酸類似物選自ADV、LMV、FCV、FTC、ETV、DAPD、TDF或DXG。
17.權(quán)利要求15或16的藥劑，其中HBV聚合酶包括位于r t結(jié)構(gòu)域的氨基酸殘基位置編號(hào)28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257的突變。
18.權(quán)利要求15或16或17的藥劑，其中HBV聚合酶包括位于rt結(jié)構(gòu)域的氨基酸殘基位置編號(hào)4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266的突變。
19.權(quán)利要求18的藥劑，其中HBV聚合酶包括選自如下位置的突變。rtA21，rtA38，rtY54，rtN76，rtL91，rtF122，rtY124，rtT128，rtQ130，rtT184，rtM204，rtS202，rtH248，rtY252，rtS21，rtN/S/T/I/V53，rtY54，rtS57，rtL91，rtS116，rtL122，rtF122，rtN124，rtY124 rtH126，rtY126，rtT128N，rtP130，rtD131，rtV134，rtY135，rtY141，rtL145，rtF151，rtL180，rtA181，rtS202，rtI204，rtK212，rtL217，rtS219，rtI235，rtN236，rtN238，sP120，sM125，sS126，sT127，sT118，sM133，sM133，sF134，sS143，sD144，sG145，sW172，sI195，sS207，sY225，間隔基L97，間隔基K115，間隔基H116，間隔基128，間隔基S137，間隔基R139，間隔基F142，rtA97，rtH126，rtS135，rtM204，PreS1N114，PreS1 T115，PreS2 F22，PreS2 V39，PreS2 P52，sL89，sT118，sF161，sE164，sI195，sI208，PreS1 E86，PreS1 N91，PreS2 P41，sQ30，sP120，sL176，sV194，rtS21，rtL122，rtN124，rtH126，rtP130，rtD131，rtY135，rtN/S/T/I/V53，rtY126，rtS202，rtI204，rtI235，sM125，sT127，sT118，sM133，sF134，sI195，sS207，sY225，rtG172，rtG174，rtP177，rtL180，rtT184，sR160，sE164，sF170，sL175，sQ181，sC/W182，sW196，sW196，sW196，sM198，sW199，sS204，sY206，sS210，sS210，sL216，sY255，rtL77，rtL77，rtL80，rtL80，rtH90，rtS117，rt125，rt128，rtQ125，rtQ125，rtY126Q，rtL128，rtT128，rtL132，rtN134，rtS 137，rtN139，rtN139，rtY141，rtV/G142，rtL147，rtK149，rtG153，rtR153，rtW153，rtW153，rtF166，rtI169，rtF178，rtI187，rtI187，rtV191，rtV191，rtN202，rtS202，rtS202，rtS213，rtV/G214，rtS219，rtS219，rtN/Q238，rtN/S/H238，rtN/S/H/T238，rtR242，rtR242，rtN248，rtI253，s118-207，s117-120，sI68，sC69，sL109，sG112，sS17，sT118，sK122，sT123，sT126，sT131，sN131，sM133，sM133，sY/F134，sC139，sK141，sD144，sG145，rtT128，rtL82，rtT135，rtT150，rtV163，rtT184，rtA200，rtF202，rtS213，rtQ215，rtS219，rtA222，rtI224，rtL229，rtL235，rtN238，rtS78，rt116DEL122，rtI163，rtL180，rtE8，rtV23，rtD31，rtY53，rtV58，rtA/S21，rtV/I/N/S/T53，rtV/I/N/S/T53，rtS/T/N/H/A54，PreS2 L11，PreS2 R17，DEL PreS2 18-21，PreS2 T30，PreS2 N54，sT13，PreS2 Q1，PreS2 Q1，rtH90，rtL/F108，rtL157，rtA181，rtV207，rtP109，rtN/H/A/S/Q238，s181，sP214，sF83，sL173，sW199，sI126，sK160，sS174，sA84，sS210，sC69，sC76，si110，sY134或sW172。
20.權(quán)利要求19的藥劑，其中HBV聚合酶包括選自如下的突變r(jià)tA21S，rtA38E，rtY54H，rtN76D，rtL91I，rtF122L，rtY124H，rtT128N，rtQ130P，rtT184G，rtM204V/I，rtS202I，rtH248N，rtY252L，rtS21A，rtN/S/T/V/53D，rtY54H，rtS57P，rtL91I，rtS116P，rtL122F，rtF122L，rtN124H，rtY124H，rtH12R，rtY126Q，rtT128N，rtP130Q，rtD131N，rtV134D，rtY135C，rtY141Y/F，rtL145M，rtF151T/F，rtL180M，rtA181T，rtS202G，rtI204V，rtK212R，rtL217R，rtS219A，rtI235I/M，rtN236T，rtN238D，sP120T，sM125T，sS126T，sT127A，sT118R，sM133L/M，sM133T，sF134V，sS143S/T，sD144A，sG145A，sW172Stop，sI195M，sS207R，sY225Y/C，間隔基L97I，間隔基K115R，間隔基H116L，間隔基L128F，間隔基S137G，間隔基R139G，間隔基F142S，rtA97V，rtH126R，rtS135Y，rtM204I，PreS 1N114D，PreS1 T115S，PreS2F22L，PreS2 V39A，PreS2 P52L，sL89V，sT118A，sF161L，sE164D，sI195M，sI208T，PreS1 E86Q，PreS1 N91K，PreS2 P41H，sQ30K，sP120T，sL176V，sV194F，rtS21A，rtL122F，rtN124H，rtH126R，rtP130Q，rtD131N，rtY135C，rtN/S/T/I/V53D，rtY126Q，rtS202G，rtI204V，rtI235L/M，sM125T，sT127A，sT118R，sM133T，sF134V，sI195M，sS207R，sY225Y/C，rtG172E，rtG174C，rtP177L，rtL180V，rtT184S，sR160N，sE164D，sF170L，sL175L/S，sQ181E/G/Q，sC/W182Y/STOP，sW196L，sW196S，sW196STOP，sM198I，sW199S，sS204T，sY206N，sS210K，sS210R，sL216STOP，sY255F，rtL77L/F，rtL77L/M/V，rtL80I，rtL80V，rtH90N/H，rtS117S/Y，rt125DELrt128，rtQ125K，rtQ125N，rtY126Q，rtL128L/M，rtT128A，rtL132L/M，rtN134G，rtS137T，rtN139H，rtN139K，rtY141Y/STOP，rtV/G142L，rtL147L/W，rtK149R，rtG153E，rtR153Q，rtW153S，rtW153Q，rtF166L，rtI169L，rtF178F/L，rtI187L，rtI187I/V，rtV191I，rtV191V/I，rtN202S，rtS202S/C，rtS202G，rtS213T，rtV/G214E，rtS219A，rtS219P，rtN/Q238H，rtN/S/H238N/K，rtN/S/H/T238/T/A/S/L，rtR242R/K，rtR242R/S，rtN248H，rtI253A，s118-207，s117-120DEL，sI68I/M，sC69F/L，sL109I/L，sG112R，sS17T，sT118R，sK122R，sT123P，sT126S，sT131N，sN131T，sM133K/M，sM133I，sY/F34S，sC139C/G，sK141E，sD144E，sG145R，rtT128T/I，rtL82M，rtT135C，rtT150A，rttV163I，rtT184S，rtA200V，rtF202V，rtS213T，rtQ215H，rtS219A，rtA222T，rtI224S，rtL229M，rtL235I，rtN238S，rtS78T，rt116DEL122，rtI163V，rtL180V，rtE8A，rtV23I，rtD31D/G，rtY53D，rtV58V/I，rtA/S21T，rtV/I/N/S/T53D，rtV/I/N/S/T53Y，rtS/T/N/H/A54Y/H，PreS2 L11L/A，PreS2 R17I，DELPreS2 18-21，PreS2 T30A，PreS2 N54H，sT13T/A，PreS2 Q1V，PreS2 Q1M，rtH90D，rtL/F108L，rtL157L/M，rtA181V，rtV207I，rtP109S，rtN/H/A/S/Q238K，s181M，sP214Q，sF83S，sL173F，sW199L，sI126T，sK160R，sS174N，sA84V，sS210N，sC69STOP/C，sC76Y，si110V/I，sY134N，sW172STOP/W，K32M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；N33D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；P34S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；H35I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/V/Q/E/G/缺失；T37W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P59S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；K60M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；F61P/S/T/W/Y/V/A/R/N/D/V/Q/E/G/H/I/L/K/M/缺失；A62R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；V63A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；D83C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/缺失；V84A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；S85T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；A86R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Y89V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；H90I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；I/L91K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/缺失；P177S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；F178P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；L179K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；L180K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；A181R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Q183E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；F183P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；T184W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；Y203V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；M204F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；L235K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N236D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；T237W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P237S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；N238D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H238I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；A238R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；S239T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；Q238E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；K239M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；L247K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N248D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H248I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；F249P/S/T/W/Y/C/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；M250F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；G251H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/缺失；和V251A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失。
21.權(quán)利要求12至20任一項(xiàng)的藥劑，其中藥劑治療性用來(lái)抑制HBV復(fù)制。
22.權(quán)利要求12至20任一項(xiàng)的藥劑，其中藥劑診斷性使用。
23.包括權(quán)利要求12至20任一項(xiàng)的藥劑與一種或多種藥物學(xué)上可接受載體和/或稀釋劑一起的組合物。
24.鑒定能夠與HBV聚合酶或其同系物、衍生物、類似物或片段相互作用并調(diào)節(jié)至少一種與所述聚合酶相關(guān)的功能活性的藥劑的方法，所述方法包括使所述聚合酶接觸藥劑并測(cè)定所述藥劑與所述聚合酶相互作用互補(bǔ)性的程度。
25.權(quán)利要求24的方法，其中HBV聚合酶來(lái)自野生型HBV。
26.權(quán)利要求24的方法，其中HBV聚合酶來(lái)自對(duì)核苷或核苷酸類似物抗性的變體HBV。
27.權(quán)利要求26的方法，其中核苷或核苷酸類似物選自ADV、LMV、FCV、FTC、ETV、DAPD、TDF或DXG。
28.權(quán)利要求26或27的方法，其中HBV聚合酶包括位于rt結(jié)構(gòu)域的氨基酸殘基位置編號(hào)28-36、39-45、59-66、69-70、73-93、167-184、198-213、230-241和245-257的突變。
29.權(quán)利要求26或27或28的方法，其中HBV聚合酶包括位于rt結(jié)構(gòu)域的氨基酸殘基位置編號(hào)4-10、24-27、46-58、67-68、71-72、94-120、165-166、185-197、214-227、242-244和258-266的突變。
30.權(quán)利要求29的方法，其中HBV聚合酶包括突變選自如下位置的突變。rtA21，rtA38，rtY54，rtN76，rtL91，rtF122，rtY124，rtT128，rtQ130，rtT184，rtM204，rtS202，rtH248，rtY252，rtS21，rtN/S/T/I/V53，rtY54，rtS57，rtL91，rtS116，rtL122，rtF122，rtN124，rtY124 rtH126，rtY126，rtT128N，rtP130，rtD131，rtV134，rtY135，rtY141，rtL145，rtF151，rtL180，rtA181，rtS202，rtI204，rtK212，rtL217，rtS219，rtI235，rtN236，rtN238，sP120，sM125，sS126，sT127，sT118，sM133，sM133，sF134，sS143，sD144，sG145，sW172，sI195，sS207，sY225，間隔基L97，間隔基K115，間隔基H116，間隔基128，間隔基S137，間隔基R139，間隔基F142，rtA97，rtH126，rtS135，rtM204，PreS1 N114，PreS1 T115，PreS2 F22，PreS2 V39，PreS2 P52，sL89，sT118，sF161，sE164，sI195，sI208，PreS1 E86，PreS1 N91，PreS2 P41，sQ30，sP120，sL176，sV194，rtS21，rtL122，rtN124，rtH126，rtP130，rtD131，rtY135，rtN/S/T/I/V53，rtY126，rtS202，rtI204，rtI235，sM125，sT127，sT118，sM133，sF134，sI195，sS207，sY225，rtG172，rtG174，rtP177，rtL180，rtT184，sR160，sE164，sF170，sL175，sQ181，sC/W182，sW196，sW196，sW196，sM198，sW199，sS204，sY206，sS210，sS210，sL216，sY255，rtL77，rtL77，rtL80，rtL80，rtH90，rtS117，rt125，rt128，rtQ125，rtQ125，rtY126Q，rtL128，rtT128，rtL132，rtN134，rtS137，rtN139，rtN139，rtY141，rtV/G142，rtL147，rtK149，rtG153，rtR153，rtW153，rtW153，rtF166，rtI169，rtF178，rtI187，rtI187，rtV191，rtV191，rtN202，rtS202，rtS202，rtS213，rtV/G214，rtS219，rtS219，rtN/Q238，rtN/S/H238，rtN/S/H/T238，rtR242，rtR242，rtN248，rtI253，s118-207，s117-120，sI68，sC69，sL109，sG112，sS17，sT118，sK122，sT123，sT126，sT131，sN131，sM133，sM133，sY/134，sC139，sK141，sD144，sG145，rtT128，rtL82，rtT135，rtT150，rtV163，rtT184，rtA200，rtF202，rtS213，rtQ215，rtS219，rtA222，rtI224，rtL229，rtL235，rtN238，rtS78，rt116DEL122，rtI163，rtL180，rtE8，rtV23，rtD31，rtY53，rtV58，rtA/S21，rtV/I/N/S/T53，rtV/I/N/S/T53，rtS/T/N/H/A54，PreS2L11，PreS2 R17，DEL PreS2 18-21，PreS2 T30，PreS2 N54，sT13，PreS2 Q1，PreS2 Q1，rtH90，rtL/F108，rtL157，rtA181，rtV207，rtP109，rtN/H/A/S/Q238，s181，sP214，sF83，sL173，sW199，sI126，sK160，sS174，sA84，sS210，sC69，sC76，si110，sY134或sW172。
31.權(quán)利要求30的方法，其中HBV聚合酶包括突變選自如下的突變。rtA21S，rtA38E，rtY54H，rtN76D，rtL91I，rtF122L，rtY124H，rtT128N，rtQ130P，rtT184G，rtM204V/I，rtS202I，rtH248N，rtY252L，rtS21A，rtN/S/T/I/V53D，rtY54H，rtS57P，rtL91I，rtS116P，rtL122F，rtF122L，rtN124H，rtY124H，rtH126R，rtY126Q，rtT128N，rtP130Q，rtD131N，rtV134D，rtY135C，rtY141Y/F，rtL145M，rtF151T/F，rtL180M，rtA181T，rtS202G，rtI204V，rtK212R，rtL217R，rtS219A，rtI235I/M，rtN236T，rtN238D，sP120T，sM125T，sS126T，sT127A，sT118R，sM133L/M，sM133T，sF134V，sS143S/T，sD144A，sG145A，sW172Stop，sI195M，sS207R，sY225Y/C，間隔基L97I，間隔基K115R，間隔基H116L，間隔基L128F，間隔基S137G，間隔基R139G，間隔基F142S，rtA97V，rtH126R，rtS135Y，rtM204I，PreS1 N114D，PreS1 T115S，PreS2F22L，PreS2 V39A，PreS2 P52L，sL89V，sT118A，sF161L，sE164D，sI195M，sI208T，PreS1 E86Q，PreS1 N91K，PreS2 P41H，sQ30k，sP120T，sL176V，sV194F，rtS21A，rtL122F，rtN124H，rtH126R，rtP130Q，rtD131N，rtY135C，rtN/S/T/I/V53D，rtY126Q，rtS202G，rtI204V，rtI235I/M，sM125T，sT127A，sT118R，sM133T，sF134V，sI195M，sS207R，sY225Y/C，rtG172E，rtG174C，rtP177L，rtL180V，rtT184S，sR160N，sE164D，sF170L，sL175L/S，sQ181E/G/Q，sC/W182Y/STOP，sW196L，sW196S，sW196STOP，sM198I，sW199S，sS204T，sY206N，sS210K，sS210R，sL216STOP，sY255F，rtL77L/F，rtL77L/M/V，rtL80I，rtL80V，rtH90N/H，rtS117S/Y，rt125DELrt128，rtQ125K，rtQ125N，rtY126Q，rtL128L/M，rtT128A，rtL132L/M，rtN134G，rtS137T，rtN139H，rtN139K，rtY141Y/STOP，rtV/G142L，rtL147L/W，rtK149R，rtG153E，rtR153Q，rtW153S，rtW153Q，rtF166L，rtI169L，rtF178F/L，rtI187L，rtI187I/V，rtV191I，rtV191V/I，rtN202S，rtS202S/C，rtS202G，rtS213T，rtV/G214E，rtS219A，rtS219P，rtN/Q238H，rtN/S/H238N/K，rtN/S/H/T238/T/A/S/L，rtR242R/K，rtR242R/S，rtN248H，rtI253A，s118-207，s117-120DEL，sI68I/M，sC69F/L，sL109I/L，sG112R，sS17T，sT118R，sK122R，sT123P，sT126S，sT131N，sN131T，sM133K/M，sM133I，sY/F134S，sC139C/G，sK141E，sD144E，sG145R，rtT128T/I，rtL82M，rtT135C，rtT150A，rtV163I，rtT184S，rtA200V，rtF202V，rtS213T，rtQ215H，rtS219A，rtA222T，rtI224S，rtL229M，rtL235I，rtN238S，rtS78T，rt116DEL122，rtI163V，rtL180V，rtE8A，rtV23I，rtD31D/G，rtY53D，rtV58V/I，rtA/S21T，rtV/I/N/S/T53D，rtV/I/N/S/T53Y，rtS/T/N/H/A54Y/H，PreS2 L11L/A，PreS2 R17I，DELPreS2 18-21，PreS2 T30A，PreS2 N54H，sT13T/A，PreS2 Q1V，PreS2 Q1M，rtH90D，rtL/F108L，rtL157L/M，rtA181V，rtV207I，rtP109S，rtN/H/A/S/Q238K，s181M，sP214Q，sF83S，sL173F，sW199L，sI126T，sK160R，sS174N，sA84V，sS210N，sC69STOP/C，sC76Y，si110V/I，sY134N，sW172STOP/W，K32M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；N33D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；P34S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；H35I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；T37W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P59S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；K60M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；F61P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；A62R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；V63A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；D83C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/缺失；V84A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失；S85T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；A86R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/YV/缺失；Y89V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；H90I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；I/L91K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/缺失；P177S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；F178P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；L179K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；L180K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；A181R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；Q183E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；F183P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；T184W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；Y203V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/缺失；M204F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；L235K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N236D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；T237W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/缺失；P237S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/缺失；N238D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H238I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；A238R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/缺失；S239T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/缺失；Q238E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/缺失；K239M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/缺失；L247K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/缺失；N248D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/V/A/R/缺失；H248I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/缺失；F249P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/M/缺失；M250F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/G/H/I/L/K/缺失；G251H/I/L/K/M/F/P/S/T/W/Y/V/A/R/N/D/C/Q/E/缺失；和V251A/R/N/D/C/Q/E/G/H/I/L/K/M/F/P/S/T/W/Y/缺失。
32.HBV聚合酶的分離片段，包括選自(i)rtE1、rtH12、rtH13、rtH160、rtA162；(ii)rtC-9、rtH-6、rtH90、rtL93、rtH234；和(iii)rtH197、rtC198、rtH216和rtC213的氨基酸殘基，其中所述片段能夠結(jié)合金屬離子。
33.權(quán)利要求32的分離的片段，進(jìn)一步包括氨基酸殘基205和206和/或氨基酸殘基33。
34.篩選能夠結(jié)合和/或抑制HBV聚合酶的藥劑的方法，所述方法包括鑒定能夠與HBV聚合酶選自以下的區(qū)域結(jié)合、相關(guān)或相互作用的化合物(i)rtE1、rtH12、rtH13、rtH160和rtA162；(ii)rtC-9、rtH-6、rtH90、rtL93、rtH234；和(iii)rtH197、rtC198、rtH216和rtC213其中所述區(qū)域是金屬離子結(jié)合位點(diǎn)。
35.權(quán)利要求34的方法，其中藥劑進(jìn)一步能夠結(jié)合通過(guò)氨基酸殘基205和206和/或氨基酸殘基83限定的HBV聚合酶區(qū)域。
36.權(quán)利要求34的方法，其中藥劑抑制或降低金屬離子和選自以下的區(qū)域或附近的氨基酸殘基的結(jié)合(i)rtE1、rtH12、rtH13、rtH160和rtA162；(ii)rtC-9、rtH-6、rtH90、rtL93、rtH234；和(iii)rtH197、rtC198、rtH216和rtC213其中所述區(qū)域是金屬離子結(jié)合位點(diǎn)。
37.權(quán)利要求36的方法，其中藥劑抑制或降低HBV聚合酶的活性。
38.通過(guò)權(quán)利要求34至36任一項(xiàng)方法鑒定的分離的藥劑。
39.包含權(quán)利要求38的藥劑和一種或多種藥物學(xué)上可接受載體和/或稀釋劑的疫苗。
40.包括能夠與選自以下氨基酸限定的HBV聚合酶區(qū)域或附近的氨基酸殘基結(jié)合、相關(guān)或相互作用的分子的診斷劑(i)rtE1、rtH12、rtH13、rtH160和rtA162；(ii)rtC-9、rtH-6、rtH90、rtL93、rtH234；和(iii)rtH197、rtC198、rtH216和rtC213其中所述區(qū)域是金屬離子結(jié)合位點(diǎn)。
41.權(quán)利要求40的診斷劑，其與報(bào)告分子連接或偶聯(lián)。
42.權(quán)利要求40的診斷劑，其中報(bào)告分子是抗體或其抗原結(jié)合片段，或報(bào)告分子與抗體或其抗原結(jié)合片段偶聯(lián)。
43.檢測(cè)HBV的方法，所述方法包括篩選權(quán)利要求41和42診斷劑的結(jié)合。
全文摘要
本發(fā)明提供了乙型肝炎病毒(HBV)聚合酶逆轉(zhuǎn)錄酶(rt)結(jié)構(gòu)域的三級(jí)結(jié)構(gòu)，從該結(jié)構(gòu)對(duì)與抗病毒藥物抗性或?qū)共《舅幬锞哂薪档兔舾卸认嚓P(guān)的變體HBV聚合酶突變進(jìn)行了作圖。本發(fā)明進(jìn)一步提供了基于三級(jí)結(jié)構(gòu)所提供的原子坐標(biāo)來(lái)鑒定、設(shè)計(jì)和/或改進(jìn)能夠調(diào)節(jié)HBV聚合酶功能活性的藥劑的方法。本發(fā)明再進(jìn)一步提供了調(diào)節(jié)HBV聚合酶功能活性的方法和用于此的藥劑。根據(jù)本發(fā)明方法鑒定的藥劑特別在治療和/或預(yù)防抗病毒藥物抗性或?qū)共《舅幬锍尸F(xiàn)降低敏感度的HBV感染中尤其有用。藥劑還可以用作診斷劑，如用來(lái)辨別抗性突變。此外，本發(fā)明使待預(yù)測(cè)的特定潛在抗病毒藥物的反應(yīng)成為可能。另外，鑒定了聚合酶中新的靶點(diǎn)。
文檔編號(hào)C07H19/00GK1835967SQ200480021455
公開(kāi)日2006年9月20日申請(qǐng)日期2004年6月11日優(yōu)先權(quán)日2003年6月13日
發(fā)明者A·I·巴塞洛繆茲, D·查默斯, M·凱珀, B·特漢申請(qǐng)人:墨爾本保健公司

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