專利名稱：：基于白三烯c4合酶(ltc4s)晶體結(jié)構(gòu)選擇或設(shè)計(jì)調(diào)節(jié)劑的方法基于白三烯C4合酶(LTC4S)晶體結(jié)構(gòu)選擇或設(shè)計(jì)調(diào)節(jié)劑的方法本發(fā)明涉及用于篩選LTC4合酶的調(diào)節(jié)劑的方法。其涉及LTC4合酶三維結(jié)構(gòu)的定義和基于其上的方法。白三烯C4(LTC4)合酶(LTC4S)是生物合成白三烯中關(guān)鍵的酶，所述白三烯是炎性和過敏性病癥，特別是支氣管哮喘的病理生理學(xué)中涉及的旁分泌激素家族(Samuelsson，B.Science(科學(xué))220,568-75(1983)；和Lewis,R.A.,Austen,K.F.&Soberman,R.J.NEnglJMed(新英格蘭醫(yī)學(xué)雜志)323,645-55(1990))。白三烯通過免疫活性細(xì)胞包括嗜中性粒細(xì)胞、嗜酸性粒細(xì)胞、嗜堿性粒細(xì)胞、肥大細(xì)胞和巨噬細(xì)胞對(duì)多種免疫學(xué)以及非免疫學(xué)刺激響應(yīng)而形成的。這些脂質(zhì)介體分為兩個(gè)主要類型，其以趨化因子LTB4、和引起痙攣的半胱氨?；?白三烯(LTC4,LTD4,和LTE4)為范例。白三烯生物合成由酶5-脂肪加氧酶(5-L0)起始，所述5-脂肪加氧酶(5-L0)將花生四烯酸轉(zhuǎn)化為不穩(wěn)定的環(huán)氧化物L(fēng)TA4,白三烯級(jí)聯(lián)中的中間產(chǎn)物。LTA4可以隨之通過酶LTA4水解酶被水解為L(zhǎng)TB4，或與GSH綴合形成LTC4,即由特異性LTC4S催化的反應(yīng)。在細(xì)胞活化過程中，白三烯生物合成中所有的關(guān)鍵酶，除1/隊(duì)4水解酶外，都形成裝配在核膜上的生物合成復(fù)合物,這提示白三烯可以具有未知的與基因調(diào)節(jié)或細(xì)胞生長(zhǎng)有關(guān)的核內(nèi)功能(Serhan，C.N.,Haeggstrom,J.Z.&Leslie,C.C.FasebJ(Faseb雜志)10，1147-58(1996))。白三烯C4，即LTC4S的天然產(chǎn)物，可以分別由Y-谷氨?；D(zhuǎn)肽酶和二肽酶裂解,從而產(chǎn)生LTD4和LTE4。同時(shí)，這三種白三烯組成以前已知的過敏性反應(yīng)的緩慢反應(yīng)底物(SRS-A),在人類呼吸系統(tǒng)中以僅僅nM濃度具有深遠(yuǎn)影響的有效的平滑肌收縮劑,其中其引起支氣管狹窄，具有增多泄漏的微血管循環(huán)和水腫形成(Samuelsson，B.Science(科學(xué))220,568-75(1983))。因此，半胱氨?；?白三烯(cys-LT)被認(rèn)為是炎癥和過敏的關(guān)鍵介質(zhì)，并在許多疾病，包括腎炎、皮炎、花粉熱、和特別是哮喘和肺纖維化中有所涉及(Lewis,R.Α.，Austen,K.F.&Soberman,R.J.NEnglJMed(新英格蘭醫(yī)學(xué)雜志)323,645-55(1990)；Beller,Τ.C.等ProcNatlAcadSciUSA(美國(guó)國(guó)家科學(xué)院學(xué)報(bào))101，3047-52(2004))。此外，cys-LT在炎癥和哮喘中的作用已經(jīng)通過分子的治療潛力和臨床應(yīng)用得到充分確證,其抑制cys-LT生物合成以及cys-LT的受體的拮抗劑(Drazen,J.Μ.，IsraeliE.Byrne，P.Treatmentofasthmawithdrugsmodifyingtheleukotrienepathway(用修飾白三烯途徑的藥物治療哮喘).N.Engl..J.Med.(新英格蘭醫(yī)學(xué)雜志)340，197-206(1999))。而且，在若干白三烯缺陷的動(dòng)物模型中觀察到減少的炎性反應(yīng)(Chen,X.S.，Sheller,j.R.,Johnson,Ε.N.&Funk,C.D.Nature(自然)372,179-182(1994)；Griffiths,!.J.,等ProcNatlAcadSciUSA(美國(guó)國(guó)家科學(xué)院學(xué)報(bào))92,517-21(1995)；和Griffiths,R.J.，等JExpMed(實(shí)驗(yàn)方法雜志)185，1123-9(1997))。另外，LTC4調(diào)節(jié)免疫響應(yīng)，例如，通過干擾淋巴細(xì)胞的特定子集、生成細(xì)胞因子、以及由B淋巴細(xì)胞釋放免疫球蛋白(Payan，D.G.，Missirian-Bastian,A.&Goetzl,Ε.J.ProcKatIAcadSciUSA(美國(guó)國(guó)家科學(xué)院學(xué)報(bào))81,3501-5(1984)；Rola-Pleszczynski,M.&Lemaire,I.JImmunol(免疫學(xué)雜志)135，3958-61(1985)；禾口Yamaoka，K.A.，Claesson,H.E.&Rosen,A.JImmunol(免疫學(xué)雜志)143，1996-2000(1989))。LTC4S眾所周知是不穩(wěn)定的18kDa膜內(nèi)在酶，已將其由KG-I和THP-I細(xì)胞純化具有明顯同質(zhì)性(Penrose，J.F.等ProcNatlAcadSciUSA(美國(guó)國(guó)家科學(xué)院學(xué)報(bào))89，11603-11606(1992)；Nicholson,I).W.等ProcNat].AcadSciUSA(美國(guó)國(guó)家科學(xué)院學(xué)報(bào))90,2015-2019(1993)。該酶的克隆和分子表征意外地揭示出LTC4S和FLAP是同源蛋白(Lam,B.K.，等ProcNatlAcadSciUSA(美國(guó)國(guó)家科學(xué)院學(xué)報(bào))91，7663-7667(1994)；Welsch,D.J.等ProcNatlAcadSciUSA(美國(guó)國(guó)家科學(xué)院學(xué)報(bào))91，9745-9749(1994))。另外的研究顯示LTC4S還疏遠(yuǎn)地與微粒體谷胱甘肽轉(zhuǎn)移酶(MGST),具體地MGST2和MGST3相關(guān)，并確定了若干與LT代謝的功能連接。因此，人MGST2和MGST3都具有LTC4合酶活性，且近期的研究顯示主要，如果不是僅僅，人臍靜脈內(nèi)皮細(xì)胞中的LTC4生成酶是MGST2，這說明該酶在血管壁中起跨細(xì)胞生物合成LTC4的作用(JakobssomP.-J.，等Prot.Sci.(蛋白質(zhì)科學(xué))8，689-692(1998))。另一種與LTC4S同源的酶是微粒體前列腺素(PG)E合酶1型(mPGES-Ι),其催化前列腺素內(nèi)過氧化物轉(zhuǎn)化為物質(zhì)PGE2,即炎癥、發(fā)燒和疼痛的重要介體CJakobsson，P..J.等ProcNatlAcadSciUSA(美國(guó)國(guó)家科學(xué)院學(xué)報(bào))96，7220-7225(1999))。同時(shí)，LTC4S,FLAP,MGSTl,MGST2，MGST3,和微粒體前列腺素(PG)E2合酶屬于稱為MAPEG(類花生酸和谷胱甘肽代謝中的膜相關(guān)蛋白)的普通蛋白超家族(Jakobsson,P.-J.,等Prot.Sci.(蛋白質(zhì)科學(xué))8,689-692(1998))。迄今，尚未獲得關(guān)于LTC4S或MAPEG家族中任何其他成員的詳細(xì)結(jié)構(gòu)信息。一些粗結(jié)構(gòu)信息已通過電子顯微鏡，即與X射線晶體學(xué)非常不同且不產(chǎn)生極小分辨率的結(jié)構(gòu)的技術(shù)獲得。因此，Schmidt-Krey等(Structure(結(jié)構(gòu))12，2009-14(2004))描述了2維晶體LTC4S的產(chǎn)生，由其可以計(jì)算出投影圖，揭示關(guān)于其四元結(jié)構(gòu)(三聚體)和跨膜螺旋基本相互關(guān)系的圖。還確定了解毒性肝酶MGST-1的低分辨率(3.2A)結(jié)構(gòu)(Holm等(2006)JMolBiol(分子生物學(xué)雜志)360,934-945。然而，盡管其公認(rèn)需要，但是LTC4S的三維結(jié)構(gòu)尚未公開。更特別地,為了提供這樣的確定需要克服的問題可以簡(jiǎn)單地解釋如下。在獲得蛋白質(zhì)分子的三維結(jié)構(gòu)中存在2個(gè)主要困難，如下文中進(jìn)一步討論地。第一個(gè)是生長(zhǎng)可再生且衍射到極小分辨率(超過2.5A)的優(yōu)質(zhì)晶體。這意味著對(duì)影響晶體生長(zhǎng)的參數(shù)諸如，僅提及一些，pH、溫度、緩沖液天性、沉淀劑天性的徹底和麻煩的研究。添加配體諸如底物類似物或抑制劑或添加其他分子對(duì)于獲得良好的晶體而言可以是很重要的。幾乎不存在關(guān)于結(jié)晶過程物理學(xué)背景的理解，這意味著關(guān)于特定蛋白的合適結(jié)晶條件的研究是獨(dú)特的，需要?jiǎng)?chuàng)造力和直覺力，且受試驗(yàn)和誤差程序的控制。蛋白質(zhì)的純度也是結(jié)晶中的關(guān)鍵參數(shù)，且合適的純度水平可以是很難,或甚至不可能獲得的。在獲得合適的晶體前,不保證可能進(jìn)行這些。應(yīng)該進(jìn)一步強(qiáng)調(diào)，所有這些問題對(duì)于膜蛋白，特別是膜內(nèi)在蛋白而言是極端難以處理的，即很難以大和充分純的量獲得。而且，膜蛋白是疏水性的，傾向于聚集，并且通過多種干擾結(jié)晶過程的去污劑被保持在溶液中。第二個(gè)主要的困難與克服X射線衍射法固有的相-問題有關(guān)。為了能夠克服該問題，必需用合適的重原子物質(zhì)諸如例如水銀、金或鉑化合物代替蛋白質(zhì)。晶體通常不能經(jīng)受住使用這些化合物的處理且關(guān)于合適替代的搜索不是直截了當(dāng)?shù)那铱梢宰兊梅浅０嘿F。另一種選擇是用硒基-甲硫氨酸(Se-Met)殘基置換所有的甲硫氨酸。這種方法需要在非標(biāo)準(zhǔn)條件下在特殊大腸桿菌(E.coli)品系中生成重組蛋白，隨后進(jìn)行關(guān)于含有Se-Met的蛋白的新的純化和重結(jié)晶。重要的是,注意到盡管Schmidt-Krey等報(bào)告了生成LTC4合酶的2維晶體(即LTC4合酶同源三聚體的單層或少量(例如小于10)層)，但是這些晶體不能用于X射線晶體學(xué)和確定該酶的三維結(jié)構(gòu)。關(guān)于使用目前的技術(shù)的X射線晶體學(xué)，必須具有三維晶體，即具有多于一層的LTC4合酶三聚體，如本領(lǐng)域中技術(shù)人員公知地。因此，LTC4S三維結(jié)構(gòu)的可靠定義應(yīng)該容許例如以視覺形式在計(jì)算機(jī)銀幕上展示該分子的形狀,然后，如果以上提及的問題可以得到解決,則可以開啟整個(gè)范圍的可能性，諸如基于合理結(jié)構(gòu)的藥物設(shè)計(jì)，例如與組合化學(xué)結(jié)合，其目的在于制備有效用于白三烯級(jí)聯(lián)相關(guān)病癥的新型藥物，以及蛋白質(zhì)-改造從而創(chuàng)建具有改變但仍有效的性質(zhì)的新型酶變體。因?yàn)長(zhǎng)TC4S被認(rèn)為是重要的藥物靶標(biāo),所以合成了它的一些抑制劑(Hutchinson,J.H.等J.Med.Chem.(醫(yī)學(xué)化學(xué)雜志)38，4538-4547(1995)；Gupta,N.，Nicholson,D.W.，F(xiàn)ord-Hutchinson，Α.W.Can.J.Physiol.Pharmacol.(生理學(xué)和藥理學(xué)雜志)75，1212-1219(1997))。由于缺少關(guān)于LTC4S三維結(jié)構(gòu)的任何可獲得的信息，如上所討論地，所以以前記述的抑制劑中沒有--種是基于其精確結(jié)構(gòu)設(shè)計(jì)的。因此,在該領(lǐng)域中存在確定LTC4S三維結(jié)構(gòu)的需要，從而設(shè)計(jì)LTC4S的更有效和選擇性抑制劑以及表現(xiàn)出甚至更有利的藥物特性的改良結(jié)構(gòu)。在本說明書中列舉或討論以前公開的文獻(xiàn)不應(yīng)該必然地被認(rèn)為是承認(rèn)該文獻(xiàn)是現(xiàn)有技術(shù)的一部分或是--般常識(shí)。我們結(jié)晶化和確定了與底物谷胱甘肽復(fù)合的LTC4S的三維結(jié)構(gòu)。這是MAPEG蛋白家族成員的第一個(gè)高分辨率三維結(jié)構(gòu)，且容許說明催化作用的結(jié)構(gòu)基礎(chǔ)和分子機(jī)制。另外，該結(jié)構(gòu)信息使得合理設(shè)計(jì)可以被開發(fā)為臨床有效抗炎性藥物的酶抑制劑成為可能。本發(fā)明的第一方面提供用于選擇或設(shè)計(jì)預(yù)期用于調(diào)節(jié)白三烯C4合酶(LTC4S)活性的化合物的方法，所述方法包括使用分子建模方法選擇或設(shè)計(jì)預(yù)期與LTC4S的催化位點(diǎn)或底物結(jié)合區(qū)(和活性位點(diǎn)一起)相互作用的化合物，其中LTC4S的催化位點(diǎn)或底物結(jié)合區(qū)的至少一部分的三維結(jié)構(gòu)與化合物的三維結(jié)構(gòu)相比較,和選擇預(yù)期與所述催化位點(diǎn)或底物結(jié)合區(qū)相互作用的化合物。本發(fā)明提供基于計(jì)算機(jī)的合理藥物設(shè)計(jì)方法，其包括提供LTC4S(蛋白)的催化位點(diǎn)或底物結(jié)合區(qū)的至少一部分的結(jié)構(gòu),如通過表I或表II的坐標(biāo)士小于2.0A,優(yōu)選小于1.5A,1.0A，或0.5A的來自所述蛋白質(zhì)主鏈原子的均方根偏差所定義地；提供候選調(diào)節(jié)分子的結(jié)構(gòu)；和使所述候選調(diào)節(jié)分子的結(jié)構(gòu)擬合所述蛋白質(zhì)的結(jié)構(gòu)。所謂術(shù)語LTC4S，包括在Lam等(1994)ExpressioncloningofacDNAforhumanleukotrieneC4synthase,anintegralmembraneproteinconjugatingreducedglutathionetoleukotrieneA4(人白三烯C4合酶，即使還原的谷胱甘肽與白三烯A4綴合的膜內(nèi)在蛋白的cDNA的表達(dá)克隆)PNAS91,7663-7667或We1sch等(1994)Mo1ecu1arcloningandexpressionofhumanleukotriene_C4synthase(人白烯-C4合酶的分子克隆和表達(dá))PNAS91,9745-9749中被稱為L(zhǎng)TC4S的多肽。LTC4S具有EC數(shù)4.4.1.20。人LTC4S多肽序列顯示如下。術(shù)語“LTC4S”用于本文中時(shí)，包括該多肽序列及其天然存在的變體。另外的動(dòng)物物種也具有與LTC4S等價(jià)的多肽,且屬于該術(shù)語的范圍。優(yōu)選地，所謂LTC4S,我們意指以下所示的LTC4S多肽序列或與其具有至少60，65，70,75，80，85，90,95或98%同一性的多肽序列。..1MetLysAspGluValAlaLeuLeuAlaAla.10.11ValThrLeuLeuGlyValLeuLeuGlnAla.20.21TyrPheSerLeuGlnVallieSerAlaArg.30·31ArgAlaPheArgValSerProProLeuThr·40.41ThrGlyProProGluPheGluArgValTyr.50.51ArgAlaGlnValAsnCysSerGluTyrPhe.60.61ProLeuPheLeuAlaThrLeuTrpValAla..70·71GlyliePhePheHisGluGlyAlaAlaAla·80.81LeuCysGlyLeuValTyrLeuPheAlaArg.90.91LeuArgTyrPheGlnGlyTyrAlaArgSer100101AlaGlnLeuArgLeuAlaProLeuTyrAla110111SerAlaArgAlaLeuTrpLeuLeuValAla120121LeuAlaAlaLeuGlyLeuLeuAlaHisPhe130131LeuProAlaAlaLeuArgAlaAlaLeuLeu140141GlyArgLeuArgThrLeuLeuProTrpAla150所渭術(shù)語LTC4S，包括被稱為任何哺乳動(dòng)物或其他LTC4S的多肽，其具有與人形式相同的氨基酸序列，其中具有至多20、15、10、9、8、7、6、5、4、3、2或1個(gè)保守或非保守置換。哺乳動(dòng)物L(fēng)TC4S的氨基酸序列是約90%—致的。因此,三維結(jié)構(gòu)也預(yù)期一致到約相同的程度。術(shù)語LTC4S不包括MAPEG家族的其他成員諸如FLAP,MGST-1，MGST-2,MGST-3或MPGES-I，如本領(lǐng)域中技術(shù)人員應(yīng)該顯而易見地。關(guān)于篩選方法或測(cè)定中使用的多肽或結(jié)構(gòu)，該術(shù)語還包括它的包括活性位點(diǎn)的片段和融合物(fusion)，如本領(lǐng)域中技術(shù)人員已知地。因?yàn)長(zhǎng)TC4S是單結(jié)構(gòu)域酶，所以認(rèn)為缺失全長(zhǎng)LTC4S序列廣大部分的片段可能不保持催化活性。然而,認(rèn)為其中缺失全長(zhǎng)LTC4S的C-末端氨基酸(例如，C-末端至多20，15，10，5，4，3，2或1個(gè)氨基酸)的片段保持催化活性。由于LTC4S的活性位點(diǎn)由來自兩個(gè)相鄰單體的氨基酸(表1和2)組成，所以單LTC4S多肽本身不足以具有酶活性。因此,為了展示催化活性,LTC4S多肽必須與另一種LTC4S多肽或替代多肽,例如FLAP多肽復(fù)合,例如,如LamBK等(1997)J.Biol.Chem.(生物化學(xué)雜志)272(21)13923-8)中所述。Lam等(1997)報(bào)告LTC4S多肽和FLAP多肽的融合物和其中LTCS內(nèi)在片段被FLAP的相應(yīng)片段替換的融合物的催化活性。認(rèn)為野生型LTC4S多肽自發(fā)裝配到催化活性復(fù)合物中優(yōu)選地，LTC4S片段或融合物保持該能力。結(jié)構(gòu)典型地(而非必須地)是保持LTC4S活性的LTC4S多肽的結(jié)構(gòu)(或結(jié)構(gòu)的一部分。例如，當(dāng)采用三聚體或二聚體形式時(shí)，LTC4S多肽典型地能夠綴合谷胱甘肽和白三烯A4。備選地或另外地，LTC4S多肽保持脂肪酸氫過氧化物酶活性。以下是能夠用于評(píng)估化合物調(diào)節(jié),例如抑制,LTC4S作用的能力的測(cè)定的實(shí)例。在該測(cè)定中，LTC4合酶催化這樣的反應(yīng)，其中底物L(fēng)TA4甲酯轉(zhuǎn)化為L(zhǎng)TC4甲酯。將純化的重組人LTC4合酶(例如表達(dá)在酵母中)溶解在25mMTris-緩沖液pH7.8并保存在-2CTC。該測(cè)定在增補(bǔ)了5raM谷胱甘肽(GSH)的磷酸鹽緩沖液(PBS)pH7.4中進(jìn)行。通過添加乙腈/MeOH/乙酸(50/50/1)終止反應(yīng)。該反應(yīng)在rt下在96孔板中進(jìn)行。用反相HPLC(Waters2795，使用OnyxMonolithicC18柱)對(duì)形成的LTC4甲酯進(jìn)行分析。流動(dòng)相由乙腈/MeOH/H2O(32.5/30/37.5)和1%乙酸組成，其pH由NH3調(diào)節(jié)至pH5.6，并用Waters2487UV檢測(cè)儀在280膽測(cè)量吸光度。將以下各項(xiàng)順序加入到每個(gè)孔中1.50μ1測(cè)定緩沖液，具有5mMGSH的PBS。2.0.5μ1處于DMSO中的測(cè)試化合物。3.2μ1處于PBS中的LTC4合酶。該溶液中的總蛋白濃度是0.025mg/ml。在室溫下溫育該板10分鐘。4.0.5μ1LTA4甲酯。Rt下溫育該板1分鐘。5.50μ1終止溶液。用HPLC分析80μ1溫育混合物。備選地,可以使用脂肪酸氫過氧化物酶活性測(cè)定。例如將0.l_0.2ygLTC4S在50μ1含有1.5mMGSH具有250pmol氫過氧化物(13-HP0D，或5-HPETE)的0.IMK-磷酸鹽pH7.5中RT溫育10分鐘。通過添加150μ1終止溶液(MeCNΗ20HOAc，50250.2，ν/ν)終止反應(yīng)。通過:RP-HPLC分析氫過氧化物向相應(yīng)醇的轉(zhuǎn)化，如上所述，使用包括MeCNΗ20HOAc，60400.1,ν/ν的流動(dòng)相和設(shè)置為235nm的UV檢測(cè)儀?？梢允褂眠@些測(cè)定或備選測(cè)定的變化，如技術(shù)人員應(yīng)該公知地。我們發(fā)現(xiàn)了具有N-末端六組氨酸標(biāo)記物的LTC4S特別有益于確定LTC4S的結(jié)構(gòu)。該融合多肽具有，例如，LTC4S活性和有益的溶解性和穩(wěn)定性特征，這使得其特別適合于結(jié)構(gòu)研究,例如,可以通過X射線晶體學(xué)方法分析的晶體的形成。認(rèn)為具有不同類型標(biāo)記物或不同長(zhǎng)度組氨酸標(biāo)記物(例如五組氨酸標(biāo)記物或七組氨酸標(biāo)記物)的融合多肽可能仍有效，但是不太可能與具有六組氨酸標(biāo)記的融合多肽一樣有效。六組氨酸標(biāo)記物的尺寸和金屬離子配位性質(zhì)被認(rèn)為是特別有益于形成良好衍射的LTC4S晶體。六組氨酸標(biāo)記物被認(rèn)為是配位二價(jià)金屬離子,例如鎳或鈷離子。認(rèn)為該晶體包括來自多于一個(gè)與金屬離子配位的LTC4S三聚體的相鄰六組氨酸標(biāo)記物。因此，該結(jié)構(gòu)可以是對(duì)具有N末端六組氨酸標(biāo)記物的LTC4S確定的結(jié)構(gòu)。特別優(yōu)選地,該結(jié)構(gòu)是通過如實(shí)施例1中所述的方法確定的結(jié)構(gòu),例如，由可使用包含去污劑的母液溶液獲得的晶體的可通過X射線分析獲得的結(jié)構(gòu)。合適的去污劑的實(shí)例是十二烷基麥芽糖苷(dodecylmaltoside)(DDM)。其他合適的去污劑的實(shí)例包括如FCYMAL"44-環(huán)己基1-丁基-β-D-麥芽糖苷1CAS#:1811.35-57-9.CYMALx"55-環(huán)己基1-戊基-β-D-麥芽糖苷1分子量494.SC23H42O11-正壬基-fg)-D-吡喃麥芽糖苷,ANAGRADE正壬基D-麥芽糖苷CAS#106402-05-5正癸基-⑧—D-吡喃麥芽糖苷,ANAGRADE正癸基-β-D-麥芽糖苷(Lowα)CAS#82494-09-5分子量482.BC22H42On正十一烷基--D-吡喃麥芽糖苷，ANAGRADE正十一烷基-β-D-麥芽糖苷(低CI)CASU253678-67-0正辛基-⑧_D-吡喃葡糖苷，ANAGRADE正辛基葡糖苷CASU:29836-26-8分子量292.4C14H2806結(jié)晶和X射線分析的其他優(yōu)選詳情如實(shí)施例1中所述。特別優(yōu)選地,該結(jié)構(gòu)由表I(缺乏谷胱甘肽；GSH的條件下確定的結(jié)構(gòu))或II(存在GSH的條件下確定的結(jié)構(gòu))中所示的結(jié)構(gòu)坐標(biāo)，或以這樣的結(jié)構(gòu)或坐標(biāo)為基礎(chǔ)或建模的結(jié)構(gòu)代表，例如，其中與蛋白質(zhì)主鏈原子的均方根偏差小于2.0A,優(yōu)選小于1.5A,1.0，或0.5Ao本申請(qǐng)?zhí)峁┻@樣的列表，其舉例說明定義與其底物、谷胱甘肽、以及去污劑分子之一復(fù)合的人LTC4S的坐標(biāo)，其定義脂質(zhì)底物白三烯A4(LTA4)的結(jié)合位點(diǎn)?；谄浯呋饔?，由谷胱甘肽和去污劑占據(jù)的兩個(gè)結(jié)合位點(diǎn)限定LTC4S的活性位點(diǎn)，且可以用作設(shè)計(jì)具有理想性質(zhì)的分子的模板。用于所述設(shè)計(jì)的方法將在F文中進(jìn)一步詳細(xì)討論。按照本發(fā)明的結(jié)構(gòu)坐標(biāo)包括在本說明書中，其作為以“X射線數(shù)據(jù)”表示的單獨(dú)部分，如表I到II，緊挨著權(quán)利要求之前。這些是LTC4S單體和等同分子的坐標(biāo)。在表I中，原子第1號(hào)-第1263號(hào)定義所述復(fù)合物的LTC4S部分。在表II中，原子第1號(hào)-第1195號(hào)涉及LTC4S而原子第1233號(hào)-第1252號(hào)涉及谷胱甘肽。涉及LTC4S的原子編號(hào)在2個(gè)表中不同，因?yàn)樵诘谝粋€(gè)表中可見更多殘基；尾部不常見于X射線結(jié)構(gòu)中。同源三聚體(或二聚體)中的各個(gè)活性位點(diǎn)由來自同源三聚體中的兩個(gè)相鄰亞基的殘基形成。在其確定中的一般條件詳述在以下實(shí)驗(yàn)部分中。如本領(lǐng)域中的技術(shù)人員認(rèn)識(shí)到，所述坐標(biāo)通常展示出某種程度的變化，這歸因于例如熱運(yùn)動(dòng)和晶體包裝的微小差異。因此，此處對(duì)連同蛋白質(zhì)和其他分子的表I-II的任何參考僅意欲舉例說明如通過使用相同的設(shè)備和方法確定地,在相同條件下限定分子構(gòu)造的坐標(biāo)。所述結(jié)構(gòu)可以是在存在與LTC4S或LTC4S活性調(diào)節(jié)劑(如下進(jìn)一步討論)，例如LTC4S活性的已知或潛在抑制劑的已知或潛在相互作用物(interactor)的條件下結(jié)晶后確定的結(jié)構(gòu)。該結(jié)構(gòu)可以,例如,是可以在缺乏谷胱甘肽(GSH)或存在GSH條件下確定的結(jié)構(gòu)。實(shí)施例1中提供關(guān)于這二者的實(shí)施例。我們發(fā)現(xiàn)了LTC4S在存在GSH的條件下結(jié)晶。備選地，GSH在最初結(jié)晶的過程中缺乏，并然后在晶體形成后滲入到其中。例如，所述結(jié)構(gòu)可以是在存在已知LTC4S抑制劑,例如被認(rèn)為與GSII結(jié)合位點(diǎn)結(jié)合的抑制劑；或被認(rèn)為在LTA4結(jié)合位點(diǎn),諸如半胱氨?；兹?，LTC4,LTD4,或LTE4結(jié)合的抑制劑,5-脂肪加氧酶抑制劑thiopyranol[2,3,4-c,d]吲哚和L-699.333，F(xiàn)LAP抑制劑MK886，或CysLT受體拮抗劑孟魯司特時(shí)結(jié)晶后確定的結(jié)構(gòu)。可以關(guān)于抑制劑形成共晶體，其能夠分別替換位于GSH底物結(jié)合腔中的GSII；或位于親脂性底物結(jié)合裂隙中的去污劑；或活性位點(diǎn)的催化部分處，如實(shí)施例1中討論地。脂質(zhì)底物和GSH對(duì)活性位點(diǎn)具有不同的親和性。因此,共晶體可以與靶向脂質(zhì)結(jié)合位點(diǎn)的化合物形成,所述靶向脂質(zhì)結(jié)合位點(diǎn)的化合物具有小于100μΜ，例如小于10μM或小于1μM的IC50(例如，使用LTA4/GSH作為底物測(cè)量地)，然而靶向GSH結(jié)合位點(diǎn)的化合物可以具有小于10mM，例如小于ImM或小于100μM的IC50(例如，使用LTA4/GSH作為底物測(cè)量地)。應(yīng)該理解,對(duì)于與不同分子的共結(jié)晶可能需要結(jié)晶條件的一些變化(例如不同的母液)。用于由本文中提供的信息開始,研究各種情形中的合適結(jié)晶條件的技術(shù)應(yīng)該是本領(lǐng)域中技術(shù)人員公知的。在一個(gè)實(shí)施方案中，共結(jié)晶可以通過使共結(jié)晶的分子擴(kuò)散到多肽的晶體，例如如實(shí)施例1中所述獲得的晶體中而進(jìn)行。這可以稱為“滲入”程序。如果存在位于活性位點(diǎn)中的GSH或去污劑,如實(shí)施例1中所討論地,則通過擴(kuò)散/滲入的共結(jié)晶可以更容易地獲得,例如,可以需要更低濃度的抑制劑，所述抑制劑具有小于10μΜ，例如小于1μM或小于IOOnM的IC50o認(rèn)為與對(duì)LTC4S具有較低親和性，例如具有毫摩爾范圍內(nèi)IC50的分子的共結(jié)晶也是可能的和有效的。例如，與被認(rèn)為與活性位點(diǎn)的僅僅一部分相互作用的小分子(“片段)的共結(jié)晶是有效的。這些小分子可以有效作為設(shè)計(jì)/構(gòu)建對(duì)LTC4S抑制劑活性具有較低IC50的較大分子的組件。本發(fā)明的另外的方面提供LTC4S多肽的三維晶形(即具有LTC4S同源三聚體的多層,例如，多于10層,優(yōu)選多于100層)，如關(guān)于本發(fā)明前述任一方面所定義地,例如，由具有N末端六組氨酸標(biāo)記物的全長(zhǎng)人LTC4S組成的多肽。三維晶形可以屬于空間群F23。晶胞可以包括48條LTC4S鏈和/或包括多個(gè)相鄰的與金屬離子配位的組氨酸標(biāo)記，如實(shí)施例1中進(jìn)步討論地(例如，關(guān)于每個(gè)LTC4S三聚體3個(gè)或關(guān)于每個(gè)晶胞12個(gè))。術(shù)語“三維晶形”應(yīng)該是本領(lǐng)域中技術(shù)人員公知的，且不包括二維(即LTC4S同源三聚體的單或至多約10層)晶體形式諸如Schmidt-Krey等(1994)中所述,見上。晶形還可以包括共結(jié)晶分子，例如，GSH或去污劑或其他已知的或潛在的與LTC4S相互作用物或LTC4S活性的調(diào)節(jié)劑，或測(cè)試化合物(例如，被認(rèn)為與活性位點(diǎn)的僅僅一部分相互作用的小分子)，其性質(zhì)相對(duì)LTC4S可能是未知的。例如，共結(jié)晶的分子,例如,測(cè)試化合物，可以是已知調(diào)節(jié)LTC4S或其他MAPEG家族成員活性的分子；或可以是LTC4模擬物或LTA4模擬物，或LTC4受體激動(dòng)劑或拮抗劑；或脂肪酸氫過氧化物或其模擬物，或其他脂肪族化合物(Thor6nS和JakobssonPJ,Eur.J.Biochem.(歐洲生物化學(xué)雜志)(2000)267(21)6428-34；Schroder0等，Biochem.Biophys.ResCommun..(生物化學(xué)和生物物理研究通訊)(2003),312(2)271-6.).已知的LTC4受體包括CysLTl,CysLT2和GPR-17(CianaP等EMBOJ(EMB0雜志)(2006)，25(19):4615_27)。例如，共結(jié)晶分子可以是對(duì)LTC4S具有小于100μΜ,典型地小于10μΜ,1μM或IOOnM的IC50的化合物。共結(jié)晶的分子可以是通過本發(fā)明的篩選/設(shè)計(jì)方法確定的化合物,如以下進(jìn)一步討論地。共結(jié)晶的分子可以是被認(rèn)為與活性位點(diǎn)的僅僅一部分相互作用并具有毫摩爾范圍內(nèi)的IC50的小化合物。本發(fā)明的另一方面因此提供用于制備本發(fā)明的晶形,或用于試圖制備本發(fā)明的晶形的方法,其包括1)提供關(guān)于本發(fā)明任一前述方法定義的LTC4S多肽；2)提供利用本發(fā)明的選擇/設(shè)計(jì)方法選擇的化合物(典型地但非必須地與LTC4S具有小于100μM,10μΜ,1μM或IOOnM的IC50；和3)對(duì)包括所述多肽和選擇的化合物的組合物進(jìn)行結(jié)晶實(shí)驗(yàn)。本發(fā)明的另外的方面提供關(guān)于本發(fā)明任一前述方面所定義的多肽制備LTC4S的活性位點(diǎn)或底物結(jié)合區(qū)(或其至少任一部分)的三維晶體或結(jié)構(gòu)；或與測(cè)試化合物結(jié)合的LTC4S的活性位點(diǎn)或底物結(jié)合區(qū)(或其至少任一部分)的三維晶體或結(jié)構(gòu)。關(guān)于測(cè)試化合物的優(yōu)選方案如上所示。如本領(lǐng)域中技術(shù)人員公知地，例如，使用與實(shí)施例1中所述的那些相似的技術(shù)，晶形可以有效用于產(chǎn)生X射線衍射數(shù)據(jù)和結(jié)構(gòu)。對(duì)于LTC4S所確定的結(jié)構(gòu),例如如本文中所述地,可以用于結(jié)構(gòu)溶解(solution)和精修中，例如如實(shí)施例1中所述。所述共結(jié)晶和由共結(jié)晶的分子確定的結(jié)構(gòu)可以有效用于分子建模和確定對(duì)于相互作用很重要的多肽和化合物的特性。這可以有效用于設(shè)計(jì)或選擇另外的測(cè)試化合物。在一個(gè)實(shí)施方案中，優(yōu)選地,預(yù)期建模的分子結(jié)合稱為“GSH底物結(jié)合腔”的結(jié)構(gòu)區(qū)(被認(rèn)為通過包括全長(zhǎng)人LTC4S的殘基Arg51,Arg30,Argl04,Gln53,Asn55,Glu58,Tyr59,Tyr93,Tyr97,Ile27,Pro37,Leul08的殘基，或其他LTC4S多肽的等價(jià)殘基形成)；“親脂性底物結(jié)合裂隙”(通過包括Ala20，Leu24,Ile27，Tyr59,Trpl16,Alall2,LeullS,LeulOS,Tyr109,Leu62,Val119,Thr66,Vall6和Leul7的殘基,或其他LTC4S多肽的等價(jià)殘基形成)；或“催化位點(diǎn)”(包括Argl04或Arg31的殘基,或其他LTC4S多肽的等價(jià)殘基)。因此，該方法可以包括比較所述化合物的結(jié)構(gòu)和以上提及的一個(gè)或多個(gè)區(qū)域的結(jié)構(gòu)(或與那些區(qū)域相互作用的區(qū)域)。表1:內(nèi)襯谷胱甘肽結(jié)合腔的殘基表1內(nèi)襯谷胱甘肽結(jié)合腔的殘基單體1|單體2ArgSlSer23Asn55Val26Glu58Ile27Tyr59Arg30Tyr93ArgSlTyr97Pro37Arg104Tyr50Leu108Gln53在表1中，ArgSl,Asn55,Glu58,Tyr59,Tyr93,Tyr97,Argl04,Arg30，禾ΠGln53是MAPEG家族成員中的高度保守氨基酸。在該位點(diǎn),GSH在來自一個(gè)單體的螺旋1和2和來自相鄰單體的3和4之間的界面處的極性袋深處結(jié)合。GSH分子與來自組成活性位點(diǎn)的兩個(gè)單體的殘基具有極性相互作用。GSH的羧酸鹽部分使得與位于結(jié)合袋基部的Arg5r和Arg30的鹽橋有效彎曲GSH并使其硫醇基團(tuán)指向在其中與Argl04’相互作用的膜界面。與GSH的另外的極性相互作用由G:[n53,Asn55，，Glu58，，Tyr59，，Tyr93，和Tyr97，進(jìn)行。還進(jìn)行了若干非極性相互作用(Ile27,Pro37和LeulOS')，由此提供使GSH最佳擬合于其結(jié)合袋。表2ΞΜ齢&.占Φ賄細(xì)<table>tableseeoriginaldocumentpage14</column></row><table>所述氨基酸定義結(jié)合去污劑DDM,即LTA4的良好模擬物的脂肪族側(cè)鏈的位點(diǎn)。在此，Trpl16形成袋頂，Tyr59，Ala20，和Leu62形成基底和側(cè)壁，而Leu115構(gòu)建限制LTA4Kω-末端進(jìn)一步侵入蛋白質(zhì)的底部。在LTA4的相反的末端，羧基基團(tuán)定位在底物結(jié)合裂隙的寬的部分內(nèi)。表3.LTC4S的催化結(jié)構(gòu)域<table>tableseeoriginaldocumentpage15</column></row><table>在以上表1-3中，LTC4S的氨基酸序列編號(hào)從最初的Met開始，并由此與SEQIDNO1中的編號(hào)相同。表1-3中列出的殘基可能定義關(guān)于同源酶，即,MAPEG家族的其他成員的普遍活性位點(diǎn)。優(yōu)選地，LTC4S的活性位點(diǎn)或底物結(jié)合區(qū)的至少一部分的三維結(jié)構(gòu)是均如上定義的“GSH底物結(jié)合腔”;“親脂性底物結(jié)合裂隙”；和/或“催化位點(diǎn)”或相互作用區(qū)的至少一部分的三維結(jié)構(gòu),并選擇預(yù)期與所述的“GSH底物結(jié)合腔”;“親脂性底物結(jié)合裂隙”；和！或“催化位點(diǎn)”或LTC4S的相互作用區(qū)相互作用的化合物。備選地，該化合物可以結(jié)合所述LTC4S多肽的一部分，該部分不是“GSH底物結(jié)合腔”；“親脂性底物結(jié)合裂隙”；和/或“催化位點(diǎn)”或LTC4S的相互作用區(qū)，例如由此干擾底物分子的結(jié)合或其進(jìn)入催化位點(diǎn)。在另一個(gè)實(shí)例中,所述化合物可以結(jié)合LTC4S的--部分,從而通過變構(gòu)作用減少所述多肽的活性。該變構(gòu)作用可以是參與LTC4S活性的天然調(diào)節(jié)的變構(gòu)作用。所述化合物可以結(jié)合LTC4S的一部分,所述部分參與同源多聚體亞基之間的相互作用。被認(rèn)為參與亞基之間相互作用的殘基顯示在下表中。亞基表示為亞基A、B和C,其中顯示A與B和A與C的相互作用。表4<table>tableseeoriginaldocumentpage16</column></row><table><image>imageseeoriginaldocumentpage17</image><table>tableseeoriginaldocumentpage18</column></row><table><image>imageseeoriginaldocumentpage19</image><formula>formulaseeoriginaldocumentpage20</formula><table>tableseeoriginaldocumentpage21</column></row><table><table>tableseeoriginaldocumentpage22</column></row><table>因此，本發(fā)明的另一方面提供用于選擇或設(shè)計(jì)預(yù)期調(diào)節(jié)白三烯C4合酶(LTC4S)活性的化合物的方法，所述方法包括使用分子建模方式選擇或設(shè)計(jì)預(yù)期與LTC4S的亞基相互作用區(qū)相互作用的化合物的步驟，其中LTC4S的亞基相互作用區(qū)的至少一部分的三維結(jié)構(gòu)與化合物的三維結(jié)構(gòu)比較,和選擇預(yù)期與所述底物相互作用區(qū)相互作用的化合物。涉及亞基相互作用區(qū)的殘基顯示在前述表4中。應(yīng)該理解，化合物可以具有預(yù)期與LTC4S的多于一個(gè)部分,例如LTC4S活性位點(diǎn)的多于一個(gè)部分相互作用的組成部分。例如，化合物可以具有與LTC4S的GSH底物結(jié)合腔相互作用的組成部分，如上討論地；和另一個(gè)與LTC4S的不同部分,例如與“親脂性底物結(jié)合裂隙”；和/或“催化位點(diǎn)”，即與活性位點(diǎn)的其他部分相互作用的組成部分。用于進(jìn)一步測(cè)試的化合物可以由預(yù)期結(jié)合LTC4S的不同部分，例如LTC4S活性位點(diǎn)的不同部分的組成部分(其可能分別非常小)裝配。三維結(jié)構(gòu)可以通過采用二維形式的計(jì)算機(jī),例如在計(jì)算機(jī)屏幕上顯示。比較可以利用所述二維顯示進(jìn)行。以下涉及分子建模技術(shù)Blundell等(1996)Stucture-baseddrugdesign(基于結(jié)構(gòu)的藥物設(shè)計(jì))Nature(自然)384,23-26；Bohra(1996)Computationaltoolsforstructure-basedliganddesign(用于基于結(jié)構(gòu)的配體設(shè)計(jì)的計(jì)算工具)ProgBiophysMolBiol(生物物理學(xué)和分子生物學(xué)進(jìn)展)66(3)，197-210;Cohen等(1990)JMedChem(Ε學(xué)化學(xué)雜志)33，883-894;Navia等(1992)CurrOpinStructBiol(當(dāng)前結(jié)構(gòu)生物學(xué)觀點(diǎn))2,202-210。以下計(jì)算機(jī)程序，例如，可以有效用于進(jìn)行本發(fā)明這個(gè)方面的方法GRID(Goodford(1985)JMedChem(醫(yī)學(xué)化學(xué)雜志)28，849-857；可獲自MolecularDiscovery(分子探索)，Pinner,UK)；MOE(ChemicalComputingGroup(化學(xué)計(jì)算小組)，蒙特利爾，魁北克,加拿大)；AUTODOCK(Goodsell等(1990)ProteinsStructure,FunctionandGenetics(蛋白質(zhì)結(jié)構(gòu)、功能和遺傳學(xué))8,195-202；可獲自ScrippsResearchInstitute(斯克利普斯研究所)，LaJolla,CA,美國(guó))；DOCK(Kuntz等(1982)JMolBiol(分子生物學(xué)雜志)161，269-288；可獲自theUniversityofCalifornia(加利福尼亞大學(xué))，舊金山，CA)；LUDI(Bohm(1992)jCompAidMolecDesign(計(jì)算機(jī)協(xié)助的分子設(shè)計(jì)雜志)6，61-78；可獲自Accelrys,圣地亞哥，CA，美國(guó))；Sybvl(TriposAssociates,StLouis,M0，美國(guó))；Gaussian03，例如修訂版D(Gaussian，Inc.(高斯公司)，Pittsburgh,PA，美國(guó))；AMBER(UniversityofCaliforniaatSanFrancisco(加利福尼亞大學(xué)舊金山分校)，舊金山，CA,美國(guó))；QUANTA(AcceIrys,圣地亞哥，CA,美國(guó))；和InsightII(Accelrys,圣地亞哥,CA,美國(guó)).程序可以在例如SiliconGraphics,IBMRISC/6000,或RedHatEnterpriseLinux工作站上運(yùn)行?？梢?，例如，如實(shí)施例2中所述，或通過利用程序諸如Unity(TriposAssociates，StLouis,MO,美國(guó))或ChemFinder(CambridgeSoft(劍橋軟件),Cambridge,ΜΑ,美國(guó))的新配體亞結(jié)構(gòu)搜索使用若干silico方法。采用(或預(yù)期)天然配體(LTA4或GSH)或其能夠結(jié)合LTC4S的部分的基本結(jié)構(gòu)，并將其(例如疏水性和帶電實(shí)體)多種結(jié)構(gòu)特征提交給將搜索一組關(guān)于含有該亞結(jié)構(gòu)的化學(xué)品的化學(xué)品公司目錄的程序。例如，GSH的末端的結(jié)構(gòu)可以有效用于搜索可以與GSH結(jié)合袋或催化位點(diǎn)相互作用的化合物，同時(shí)LTA4的結(jié)構(gòu)，例如其長(zhǎng)度,可以有效用于搜索與親脂性底物結(jié)合裂隙相互作用的化合物。然后，例如可以利用計(jì)算機(jī)或通過眼睛篩選這些化合物，以獲得不能與催化位點(diǎn)的部分，例如GSII底物結(jié)合腔(或其他部分，如上討論)相互作用的組，因?yàn)椤?，它們太大或具有空間或帶電位阻,并將其丟棄。將剩余化學(xué)品提交到PRODRG服務(wù)器并為這些化學(xué)品構(gòu)建拓?fù)洌∽鴺?biāo)。將這些化學(xué)品建模到結(jié)構(gòu)中，由此選擇可能能夠結(jié)合GSH底物結(jié)合腔/親脂性底物結(jié)合裂隙/催化位點(diǎn)/相互作用區(qū)的化學(xué)品。PRODRG程序的其他詳細(xì)信息可獲自http//davapcl.bioch.dundee.ac.uk/programs/prodrg/prodrg.html0備選的方法是使用PRODRG用于由小分子PDB文件生成GR0M0S/M0L2/WHATIF拓?fù)浜蜌湓游恢玫墓ぞ?。由天然配體幵始，技術(shù)人員可以計(jì)算地用多種新基團(tuán)改變配體上各個(gè)位點(diǎn)上的所有可能的基團(tuán)，而蛋白質(zhì)坐標(biāo)和配體主鏈坐標(biāo)保持固定。然后針對(duì)阻礙、排斥和吸引篩選結(jié)果。起始化合物可以最初通過用于對(duì)LTC4S酶活性作用的篩選來選擇(例如，使用LTAdt為底物)；然后與結(jié)構(gòu)比較；用作用于設(shè)計(jì)可以然后通過進(jìn)一步建模和/或合成和評(píng)估測(cè)定的其他化合物的基礎(chǔ)，如以下進(jìn)一步所討論地。然后可以對(duì)選擇的化合物進(jìn)行排序或合成和評(píng)估，以獲得一種或多種結(jié)合和/或調(diào)節(jié)LTC4S活性的能力?？梢杂肔TC4S多肽對(duì)化合物進(jìn)行結(jié)晶化并確定任何復(fù)合物的結(jié)構(gòu)。本發(fā)明的方法還可以包括提供、合成、純化和/或配制如上所述利用計(jì)算機(jī)建模選擇的化合物的步驟；和評(píng)估該化合物是否調(diào)節(jié)LTC4S活性的步驟?？梢耘渲圃摶衔镆杂糜谒幬镉猛?例如用于動(dòng)物或人的體內(nèi)實(shí)驗(yàn)中。因此,本發(fā)明提供基于結(jié)構(gòu)設(shè)計(jì)LTC4S抑制劑的方法。所述方法基于,例如,所述坐標(biāo)，或優(yōu)選定義選擇區(qū)域的坐標(biāo)，作為模板從而合成具有強(qiáng)烈和特異性結(jié)合特性抑制劑的應(yīng)用。更具體地，所述方法可以首先單獨(dú)地或與組合化學(xué)結(jié)合使用常規(guī)有機(jī)合成，其中合成產(chǎn)物的結(jié)構(gòu)再進(jìn)一步通過酶和抑制劑的結(jié)晶化循環(huán)精修，隨后進(jìn)行另一個(gè)化學(xué)合成,進(jìn)--步精修其產(chǎn)物，等?？梢赃x擇調(diào)節(jié)LTC4S活性的化合物。例如，可以選擇增加LTC4S活性的化合物，或可以選擇降低LTC4S活性的化合物。其中各種類型的化合物可以是有效的情形(或這樣的化合物是用于對(duì)其進(jìn)一步研究或化合物設(shè)計(jì)的起始點(diǎn))顯示如下。可以評(píng)估化合物調(diào)節(jié)LTC4S針對(duì)LTA4(5S,5,6_氧-7,9_反式_11,14-順式二十碳四烯酸(eicosatetraenoicacid))的活性的能力。所述評(píng)估還可以以微量滴定板形式或適合于高通量篩選的其他形式進(jìn)行。該評(píng)估可以利用本領(lǐng)域中技術(shù)人員公知的酶測(cè)定技術(shù)和如下所述地進(jìn)行。所述測(cè)定中使用的LTC4S多肽可以是保持LTC4S活性的LTC4S多肽，如上所討論地。例如，可以使用包括全長(zhǎng)人LTC4S或包括人LTC4S片段,例如缺少至多C-末端20，10，5，4，3，2或1個(gè)氨基酸的片段的多肽，如本領(lǐng)域中技術(shù)人員應(yīng)該清楚地。任何這樣的活性片段必須與互補(bǔ)片段同時(shí)存在，以形成活性二聚體或三聚體，因?yàn)榛钚晕稽c(diǎn)包括來自2個(gè)相鄰亞基的殘基認(rèn)為裝配為這樣的二聚體或三聚體自發(fā)發(fā)生,但是它們也可以使用蛋白質(zhì)工程中標(biāo)準(zhǔn)技術(shù)，通過連接體相連?？梢杂糜谠u(píng)估化合物調(diào)節(jié)，例如抑制，LTC4S作用的能力的測(cè)定的實(shí)例如上所述。備選地，可以測(cè)量該化合物調(diào)節(jié)LTC4S的脂肪酸氫過氧化物酶活性的能力。合適測(cè)定的實(shí)例如上所述。當(dāng)預(yù)期結(jié)合LTC4S活性位點(diǎn)的化合物應(yīng)該調(diào)節(jié)LTC4S的LTC4S活性時(shí)(例如通過對(duì)LTA4的作用評(píng)估)，LTC4S的其他活性或性質(zhì)可能可以受到調(diào)節(jié)，例如亞基相互作用或與其他多肽(例如其他MAPEG家族成員，例如FLAP)相互作用，磷酸化(GuptaN等HiBSLett.(FEBS書信)(1999)449(1):66-70),或二價(jià)陽離子的作用(Nicho！sonDW等Eur.J.Biochem.(歐洲生物化學(xué)雜志)(1992)209(2):725_34),或分子內(nèi)相互作用或與其他LTC4S或FLAP單體或二聚體的相互作用(MandalAK等ProcNatlAcadSciUSA(美國(guó)國(guó)家科學(xué)院學(xué)報(bào))(2004)101(17):6587-92)的調(diào)節(jié)。如上注意到地,選擇或設(shè)計(jì)的化合物可以進(jìn)行合成(如果尚未合成)或純化并測(cè)試其對(duì)LTC4S(或具有LTC4S活性的片段、變體或融合物)的作用，例如其對(duì)LTC4S活性的作用。所述化合物可以針對(duì)其對(duì)LTC4S多肽或?qū)ζ渲写嬖贚TC4S的細(xì)胞或組織的作用在體外篩選中測(cè)試。所述細(xì)胞或組織可以包含內(nèi)源LTC4S和/或可以包含外源LTC4S(包括作為處理編碼LTC4S的內(nèi)源核酸的結(jié)果表達(dá)的LTC4S)。所述化合物可以在離體或體內(nèi)篩選中測(cè)試，其可以使用轉(zhuǎn)基因動(dòng)物或組織。還可以測(cè)試所述化合物，從而在例如由于敲除或擊倒LTC4S基因的一個(gè)或多個(gè)拷貝而不包含LTC4S(或包含減少量的LTC4S的)細(xì)胞、組織或器官中比較。合適的測(cè)試對(duì)于本領(lǐng)域中技術(shù)人員而言應(yīng)該是清楚的,且實(shí)例包括評(píng)估炎癥的動(dòng)物或離體模型中的作用。合適的模型的實(shí)例包括酵母聚糖誘導(dǎo)的腹膜炎和作為過敏性哮喘模型的卵清蛋白-敏化的小鼠。所述化合物可以在人炎癥的離體模型中，例如在人外周血或人臍帶血上，或在分離自人外周血或人臍帶血的細(xì)胞上，例如在白細(xì)胞,例如嗜中性粒細(xì)胞,嗜酸性粒細(xì)胞，或肥大細(xì)胞上測(cè)試。化合物也可以經(jīng)歷其他測(cè)試,例如，毒學(xué)或代謝測(cè)試,如本領(lǐng)域中技術(shù)人員公知地。結(jié)合親脂性底物結(jié)合裂隙的化合物可以是還能夠結(jié)合LTC4S產(chǎn)物受體，即例如在細(xì)胞,諸如肥大細(xì)胞上的LTC4受體的化合物。LTC4受體的實(shí)例包括CysLTl,CysLT2和GPR-17。因此,所述化合物可以有效用作LTC4拮抗劑或激動(dòng)劑。還可以進(jìn)行適當(dāng)?shù)臏y(cè)試，以確定是否是這種情形。優(yōu)選地，LTC4S是這樣的多肽，其由上文所指的LTC4S序列的氨基酸序列或其天然存在的等位基因變體組成。優(yōu)選地,所述天然存在的等位基因變體是哺乳動(dòng)物的,優(yōu)選人的。LTC4S可以是融合多肽,例如,具有N末端六組氨酸標(biāo)記物或FLAP的融合多肽,如上所討論地。特別優(yōu)選地，盡管不是必需地,但是LTC4S的變體或片段或衍生物或融合物，或變體或片段或衍生物的融合物具有全長(zhǎng)人LTC4S關(guān)于LTA4的谷胱甘肽的綴合物的酶活性的至少30%。更優(yōu)選的是,如果所述LTC4S的變體或片段或衍生物或融合物,或所述變體或片段或衍生物的融合物具有LTC4S關(guān)于LTA4的谷胱甘肽的綴合物的酶活性的至少50%，優(yōu)選至少70%和更優(yōu)選至少90%。然而,應(yīng)該理解，缺乏酶活性的變體或融合物或衍生物或片段仍然可以是有效的，例如通過與另一種多肽相互作用。因此,缺乏酶活性的變體或融合物或衍生物或片段可以有效地用在結(jié)合測(cè)定中，其可以用于,例如,本發(fā)明的方法,其中測(cè)量對(duì)本發(fā)明的突變LTC4S和化合物的相互作用的調(diào)節(jié)。所謂多肽的“變體”,我們包括插入、缺失和置換,保守的或非保守的。具體地，我們包括多肽的變體，其中所述變化不充分改變所述多肽的活性,例如LTC4S的或LTC4S活性，如上所述。所謂“保守的置換”意指組合諸如Gly，Ala；Val,lie,Leu；Asp,Glu；Asn,Gln；Ser,Thr；Lys,Arg；禾ΠPhe,Tyr0本文中使用IUPAC-IUB生物化學(xué)命名委員會(huì)的單和三字母氨基酸編碼。具體地，Xaa代表任何氨基酸。優(yōu)選地,Xaa代表天然存在的氨基酸。優(yōu)選地,所述氨基酸是L-氨基酸。特別優(yōu)選的是，如果LTC4S變體具有這樣的氨基酸序列，所述氨基酸序列具有與上文所指的LTC4S的氨基酸序列至少65%的同一性(例如在Lam等(1994)中，見上)，更優(yōu)選地與以....Ll定義的氨基酸序列具有至少70%，71%，72%，73%或74%，更優(yōu)選至少75%，還更優(yōu)選至少80%,進(jìn)一步優(yōu)選至少85%，更進(jìn)一步優(yōu)選至少90%和最優(yōu)選至少95%或97%的同一性。兩種多肽之間的百分比序列同一性可以使用合適的計(jì)算機(jī)程序,例如UniversityofWisconsin(威斯康辛大學(xué))GeneticComputingGroup(遺傳計(jì)算小組)的GAP程序確定，且應(yīng)該理解,針對(duì)其序列被最佳比對(duì)的多肽計(jì)算百分比同一性。比對(duì)可以備選地利用Clusta丨W程序(Thompson等(1994)NuclAcidRes(核酸研究)22,4673-4680)進(jìn)行。所用參數(shù)可以如下緊密配對(duì)比對(duì)參數(shù):K-tuple(字)長(zhǎng)；1，窗口尺寸；5，縫隙扣分；3，頂對(duì)角線數(shù)量；5.評(píng)分方法x%。多比對(duì)參數(shù)縫隙開啟扣分；10，縫隙延長(zhǎng)扣分；0.05。評(píng)分矩陣BLOSUM。優(yōu)選地，LTC4S具有與Argl04或Arg31；和/或Arg51,Arg30,Arg104,Gln53,Asn55,Glu58,Tyr59,Tyr93,Tyr97,Ile27，Pro37，LeulOS(GSIi底物結(jié)合腔殘基)；和任選地還有Ala20,Leu24,1!e27,Tyr59,Trpl16,Alal12,Leul15,Leu108,Tyr109,Leu62,Val119,Thr66,Vall6和Leul7(親脂性底物結(jié)合裂隙殘基)等價(jià)的相同或保守殘基。對(duì)相同或保守殘基理想的其他殘基包括以上表1，2，3或4中列出的其他殘基。本發(fā)明的另一方面提供突變的LTC4S多肽，其中與全長(zhǎng)人LTC4S的Arg51，Arg30，Arg104,G!n53,Asn55,G!u58,Tyr59,Tyr93,Tyr97,Ile27,Pro37,Leu108,Ala20,Leu24,Ile27,Tvr59,Trpl16,Alall2,LeullS,LeulOS,Tvrl09,Leu62,Valll9,Thr66,Vall6和Leu17或Arg31等價(jià)的一個(gè)或多個(gè)殘基突變。本發(fā)明涉及LTC4S的突變形式，其突變形式包括下表5-7中定義的一種或多種突變,其中氨基酸以單字母編碼給出。因此,R51G/A/V/L/I/S/T/D/E/N/Q/H/K/P/C/M/F/Y/W表示采用LTC4S編號(hào)制的殘基精氨酸51被修飾為丙氨酸、纈氨酸、亮氨酸等。表5活性位點(diǎn)(GSH結(jié)合位點(diǎn))中的突變R30G/A/V/L/I/S/T/D/E/N/Q/H/K/P/C/M/F/Y/W5(1)R5KVA/V/L/I/S/T/D/E/N/Q/H/K/P/C/M/F/Y/W5(2)Q53G/A/V/L/I/S/T/D/E/N/R/H/K/P/C/M/F/Y/ff5(3)N55G/A/V/L/I/S/T/D/E/R/Q/H/K/P/C/M/F/Y/W5(4)Y^miκιwivsni》m、ni\\iyvιqiiYΙ\Ι5⑶Y59G/A/V/L/I/S/T/I)/E/N/Q/R/H/K/P/C/M/F/ff5(6)Y93G/A/V/L/I/S/T/D/E/N/Q/R/H/K/P/C/M/F/ff5(7)Y97G/A/V/L/I/S/T/D/E/N/Q/R/H/K/P/C/M/F/W5(8)Rl04G/A/V/L/I/S/T/D/E/N/Q/H/K/P/C/M/F/Y/ff5(9)表6活性位點(diǎn)(LTA4結(jié)合位點(diǎn))中的突變A20G/V/L/I/S/T/D/E/N/Q/R/H/K/P/C/M/F/Y/ff6(1)Y59G/A/V/L/I/S/T/D/E/N/Q/R/H/K/P/C/M/F/W6(2)Ki^ι^ι^νιχι6⑶L115G/A/V/1/S/T/D/E/N/Q/R/H/K/P/C/M/F/Y/W6(4)W116G/A/V/L/I/S/T/D/E/N/Q/R/H/K/P/C/M/F/Y6(5)更具體地，該實(shí)施方案涉及突變體，其包括至少2種突變的氨基酸的任意組合，或任一種以上提及的突變序列，或選自由序列號(hào)(5)1-9’6(卜5)組成的組中的任何單獨(dú)的一個(gè)氨基酸突變。突變的LTC4S可以有效用于確定目的多肽或化合物與LTC4S....Ll的何處相互作用。例如，可以測(cè)量和比較化合物(包括多肽)結(jié)合突變的和未突變的LTC4S，或調(diào)節(jié)LTC4S的活性的能力。本發(fā)明的另--方面提供編碼本發(fā)明突變LTC4S多肽的多核苷酸。本發(fā)明的另一方面提供適合于表達(dá)本發(fā)明突變LTC4S的重組多核苷酸。本發(fā)明的另外方面提供包括本發(fā)明多核苷酸的宿主細(xì)胞。本發(fā)明的另一方面提供制備本發(fā)明突變的LTC4S的方法,所述方法包括培養(yǎng)本發(fā)明的表達(dá)所述突變的LTC4S的宿主細(xì)胞和分離所述突變的LTC4S。本發(fā)明的另一方面提供可通過以上方法獲得的突變的LTC4S。本發(fā)明的這些方面的實(shí)例可以由本領(lǐng)域中技術(shù)人員利用常規(guī)方法制備。例如，以上突變的LTC4S可以通過本領(lǐng)域中公知的方法,例如，利用分子生物學(xué)方法或自動(dòng)化化學(xué)肽合成法制備。應(yīng)該理解，肽模擬(peptidomimetic)化合物也可以是有效的。因此，所謂“多肽”或“肽”，我們不僅包括其中氨基酸殘基通過肽(ΟΗν)鍵相連的分子，而且還包括其中肽鍵翻轉(zhuǎn)的分子。設(shè)計(jì)和制備肽模擬化合物的方法應(yīng)該是本領(lǐng)域中技術(shù)人員已知的。本發(fā)明還提供確定或表征調(diào)節(jié)LTC4S活性的化合物的方法,其包括確定所述化合物對(duì)本發(fā)明LTC4S活性的作用，或所述化合物結(jié)合所述本發(fā)明突變LTC4S的能力的步驟。所述方法還可以包括確定所述化合物對(duì)LTC4S活性的作用，或所述化合物結(jié)合在所述殘基處不突變的LTC4S的能力。例如，如技術(shù)人員應(yīng)該清楚地，比較化合物對(duì)野生型(未突變的)LTC4S和其中殘基(例如測(cè)試化合物，例如由計(jì)算機(jī)建模研究預(yù)測(cè)與之相互作用的殘基)突變的突變LTC4S的作用可以是有幫助的，從而驗(yàn)證或所述化合物如預(yù)期結(jié)合。應(yīng)該理解LTC4S或突變LTC4S可以是包括標(biāo)記物的融合蛋白，例如,從而幫助純化或結(jié)晶化，例如六組氨酸標(biāo)記物,如實(shí)施例1中所述。本發(fā)明的另一方面提供有效用于執(zhí)行本發(fā)明前述方面的方法的部分的試劑盒，包括(1)本發(fā)明的突變LTC4S和(2)不如此突變的相應(yīng)LTC4S。所述LTC4S多肽關(guān)于與化合物(其可以是多肽)相互作用或結(jié)合的能力可以通過任何檢測(cè)/測(cè)量蛋白質(zhì)/蛋白質(zhì)相互作用或其它化合物！蛋白質(zhì)相互作用的方法測(cè)量，如下文進(jìn)一步討論。合適的方法包括這樣的方法，諸如，例如，酵母雙雜交相互作用，共純化，ELISA，共免疫沉淀和表面等離子體共振法。因此，LTC4S多肽可以被認(rèn)為能夠與多肽或其他化合物結(jié)合或相互作用，條件是通過ELISA、共免疫沉淀或表面等離子體共振法或通過酵母雙雜交相互作用或共純化法可以檢測(cè)到LTC4S多肽和所述化合物或多肽之間的相互作用。優(yōu)選地，所述相互作用可以利用表面等離子體共振法檢測(cè)。表面等離子體共振法是本領(lǐng)域中技術(shù)人員公知的。技術(shù)記述在，例如，0'ShannessyDJDeterminationofkineticrateandequilibriumbindingconstantsformacromolecularinteractionsacritiqueofthesurfaceplasmonresonanceliterature(石角定大分子才目互作用白勺動(dòng)力學(xué)速度和平衡結(jié)合常數(shù)表面等離子體共振文獻(xiàn)的評(píng)論).CurrOpinBiotechnol(當(dāng)前生物技術(shù)觀點(diǎn)).1994年2月；5(1)65-71；FivashM，TowlerEM，F(xiàn)isherRJBIAcoreformacromolecularinteraction(用于大分子相互作用的BIAcore)_CurrOpinBiotechnol(當(dāng)前生物技術(shù)觀點(diǎn))·1998年2月；9(1):97_101；MalmqvistMBIACORE··cinaffinitybiosensorsystemforcharacter!z&itionofbiomolecularinteractions(BIACORE用于表征生物分子相互作用的親和性生物傳感器系統(tǒng)).BiochemSocTrans(生物化學(xué)協(xié)會(huì)學(xué)報(bào)).1999年2月；27(2):335_40。如上所示，可以評(píng)估所述化合物對(duì)LTC4S的LTC4S活性的作用?？梢赃x擇降低LTC4S的LTC4S活性的化合物。這樣的化合物可以由此有效用于治療這樣的病癥，其中需要抑制或減少例如LTC4,LTD4或LTE4的形成,或其中需要抑制或削弱CysLT受體(例如Cys-LT1或Cys-LT2)的活化。本發(fā)明的化合物還可以抑制微粒體谷胱甘肽S-轉(zhuǎn)移酶(MGSTs)，諸如MGST-I,MGST-II和/或MGST-III，由此抑制或減少LTD4,LTE4或，特別是，LTC4的形成。由此預(yù)期所述化合物有效用于治療可以由抑制白三烯(諸如LTC4)產(chǎn)生(即合成和/或生物合成)受益的病癥,例如呼吸病癥和/或炎癥?？梢赃M(jìn)行其他測(cè)試,從而評(píng)估所述化合物治療這樣的病癥和/或炎癥的適合性，如本領(lǐng)域中技術(shù)人員應(yīng)該公知的。術(shù)語“炎癥”應(yīng)該被本領(lǐng)域中的技術(shù)人員理解為包括特征為局部或全身保護(hù)性響應(yīng)的任何病癥，其可以由物理外傷，感染,慢性疾病，諸如上文中提及的那些,和/或針對(duì)外部剌激的化學(xué)和/或生理學(xué)反應(yīng)(例如過敏響應(yīng)的一部分)進(jìn)行激發(fā)。任何這樣的響應(yīng)可以通過例如發(fā)熱、腫脹、疼痛、赤紅、血管擴(kuò)張和/或增加的血流、白血細(xì)胞侵入受影響的區(qū)域、缺失功能和/或已知與炎癥病癥有關(guān)的任何其他癥狀顯現(xiàn)，所述任何這樣的響應(yīng)可以起破壞、稀釋或隔離有害試劑和受傷害組織的作用。術(shù)語“炎癥”因此還應(yīng)該被理解為包括任何炎性疾病、病癥或病況本身，任何具有與其相關(guān)的炎性成分的病況，和/或任何特征為以炎癥作為癥狀的病況，其中特別包括急性、慢性、潰瘍性、特異性、過敏性和壞死性炎癥，和本領(lǐng)域中技術(shù)人員已知的其他炎癥形式。為了本發(fā)明的目的，該術(shù)語因此還包括炎性疼痛、一般疼痛和/或發(fā)燒。因此,這樣的化合物可以有效用于治療過敏病癥,哮喘，兒童哮喘,慢性阻塞性肺病，支氣管肺發(fā)育異常，囊性纖維變性，間質(zhì)肺病(例如結(jié)節(jié)病，肺纖維化，硬皮病肺病，和肺炎中的一般間質(zhì))，耳鼻喉疾病(例如，鼻炎，鼻息肉，和中耳炎)，眼病(例如結(jié)膜炎、巨乳突性結(jié)膜炎),皮膚病(例如銀屑病,皮炎,和濕疹),風(fēng)濕病(例如類風(fēng)濕性關(guān)節(jié)炎,關(guān)節(jié)病，銀屑性關(guān)節(jié)炎,骨關(guān)節(jié)炎,全身性紅斑狼瘡,全身性硬化癥),血管炎(例如亨諾赫_舍恩萊茵紫癜，呂弗勒綜合征和川崎病)，心血管病(例如動(dòng)脈硬化硬化)，胃腸疾病(例如胃腸系統(tǒng)中的嗜酸細(xì)胞疾病，炎性腸病，腸易激綜合征，大腸炎，腹腔和胃出血)，泌尿疾病(例如腎小球腎炎，間質(zhì)膀胱炎，腎炎，腎病，腎病綜合征,肝腎綜合征,和腎毒性)，中樞神經(jīng)系統(tǒng)疾病(例如腦局部缺血,脊髓損傷,偏頭痛,多發(fā)性硬化,和睡眠障礙性呼吸)，內(nèi)分泌疾病(例如自體免疫甲狀腺炎，糖尿病相關(guān)炎癥)，蕁麻疹，過敏性反應(yīng)，血管性水腫，蛋白質(zhì)缺乏癥中的水腫，痛經(jīng)，灼燒誘導(dǎo)的氧化損傷，多重外傷，疼痛，毒油綜合征(toxicoilsyndrome),內(nèi)毒素chock,敗血癥，細(xì)菌感染(例如來自幽門螺.旋菌(Helicobacterpylori),'ΜΜΨχ^Φ-ΟΜ(Pseudomonasaerugiosa)或疾志賀氏菌(Shigelladysenteriae))，真菌感染(例如外陰陰道念珠菌病)，病毒感染(例如肝炎，腦膜炎，副流感和呼吸道合胞病毒)，鐮狀細(xì)胞性貧血,嗜酸細(xì)胞增多綜合征(hypereosinofiliesyndrome),和惡性腫瘤(例如霍奇金淋巴瘤，白血病(例如嗜酸細(xì)胞白血病和慢性骨髓性白血病)，肥大細(xì)胞增生病(mastocytos)，真核性紅細(xì)胞增多癥(polycytemivera)，和卵巢癌)。具體地,本發(fā)明的化合物可以有效用于治療過敏性病癥，哮喘，鼻炎，結(jié)膜炎，COPD,囊性纖維變性,皮炎,蕁麻疹,嗜酸細(xì)胞性胃腸疾病，炎性腸病,類風(fēng)濕性關(guān)節(jié)炎，骨關(guān)節(jié)炎和疼痛。所述化合物可以有效用于治療和/或預(yù)防性治療以上提及的病癥。增加LTC4S的LTC4合酶活性的化合物可以有效用在這樣的情形中，其中增加生成LTC4,LTD4和/或LTE4有效用于例如增強(qiáng)例如患有削弱的免疫應(yīng)答的患者中的免疫應(yīng)答。應(yīng)該理解,本發(fā)明提供用于設(shè)法鑒定可以有效調(diào)節(jié),例如增強(qiáng)或抑制，LTC4S的LTC4S活性的藥物的篩選測(cè)定法。在該方法中鑒定的化合物自身可以有效地作為藥物或它們可以代表用于設(shè)計(jì)和合成更有效的化合物的前導(dǎo)化合物。所述化合物可以是用于上述各種鑒定化合物的方法的藥物樣化合物或用于開發(fā)藥物樣化合物的前導(dǎo)化合物。應(yīng)該理解,所述方法可以有效地作為開發(fā)藥物化合物或藥物中的篩選測(cè)定法，如本領(lǐng)域中技術(shù)人員公知地。術(shù)語“藥物樣化合物”是本領(lǐng)域中技術(shù)人員公知的，其可以包括具有這樣的特征的化合物的含義,所述特征可以使其適合于用于醫(yī)學(xué),例如,作為藥物中的活性成分。因此，例如，藥物樣化合物可以是可以通過有機(jī)化學(xué),較不優(yōu)選地通過分子生物學(xué)或生物化學(xué)的技術(shù)合成的分子，和優(yōu)選是小分子，其可能小于5000道爾頓和更優(yōu)選小于1000，750或500道爾頓。藥物樣化合物可以另外展示與一種或多種特定的蛋白質(zhì)選擇性相互作用的特性并可生物獲得和/或能夠穿透細(xì)胞膜,但是應(yīng)該理解,這些特性不是必需的。術(shù)語“前導(dǎo)化合物”同樣是本領(lǐng)域中技術(shù)人員公知的,且可以包括這樣的化合物的含義，所述化合物盡管本身不適合于用作藥物(例如因?yàn)槠鋬H微弱有效地針對(duì)其預(yù)期的靶標(biāo)，其作用非選擇性，不穩(wěn)定，難以合成或具有不良生物適用性)，但是可以為設(shè)計(jì)可以具有更理想特征的其他化合物提供出發(fā)點(diǎn)。應(yīng)該理解,鑒定可以體內(nèi)調(diào)節(jié)LTC4S活性的化合物應(yīng)該是理想的。因此,應(yīng)該理解，所述方法中使用的試劑和條件可以選擇，以使得例如LTC4S和底物之間的相互作用類似于人LTC4S和天然存在的底物(例如LTA4)之間的相互作用類似。如本領(lǐng)域中技術(shù)人員公知地,不同的測(cè)定系統(tǒng)可以用于評(píng)估化合物,在其中一些中，可以最優(yōu)化測(cè)定的便利性或?qū)TC4S的作用的特異性，同時(shí)在其他中,可以例如通過評(píng)估化合物在全細(xì)胞中的作用,最優(yōu)化體內(nèi)相關(guān)性。以所述測(cè)定或在其中可以測(cè)量化合物調(diào)節(jié)LTC4S的LTC4S活性的能力的其他測(cè)定中的篩選方法中測(cè)試的化合物可以是這樣的化合物，其是已經(jīng)利用分子建模技術(shù),例如利用計(jì)算機(jī)技術(shù)選擇和/或設(shè)計(jì)(包括修飾)的。本發(fā)明還提供用于相關(guān)蛋白(以下指靶蛋白)的同源建模的方法。所渭“同源建?！币庵富讦稚渚€晶體數(shù)據(jù)預(yù)測(cè)相關(guān)MPEG家族成員結(jié)構(gòu)或基于處理表FII的坐標(biāo)數(shù)據(jù)計(jì)算機(jī)輔助從頭預(yù)測(cè)結(jié)構(gòu)?！巴唇！睌U(kuò)展到靶MAPEG蛋白，其與人LTC4S蛋白有關(guān)，所述人LTC4S蛋白的結(jié)構(gòu)已經(jīng)在所附實(shí)施例中確定了。還擴(kuò)展到LTC4S突變體。通常,所述方法涉及通過比對(duì)氨基酸序列，比較表I或11:的LTC4S蛋白和靶MAPEG家族成員蛋白的氨基酸序列。然后比較序列中的氨基酸,并將同源的(指“相應(yīng)區(qū)域”)氨基酸組分組到一起。該方法鑒定多肽的保守區(qū)，并解釋氨基酸插入或缺失?？紤]到由LTC4S獲得的結(jié)構(gòu)信息，MAPEG家族序列的比對(duì)在實(shí)施例1中討論,并且比對(duì)顯示在圖6中。氨基酸序列之間的同源性可以備選地或另外地利用可商購的運(yùn)算法則確定,如上討論地。一旦比對(duì)具有已知和未知結(jié)構(gòu)的多肽的氨基酸序列，具有已知結(jié)構(gòu)的多肽的計(jì)算機(jī)表示法中的保守氨基酸結(jié)構(gòu)被變換為靶蛋白的相應(yīng)氨基酸。例如，已知結(jié)構(gòu)的氨基酸序列中的酪氨酸可以被苯丙氨酸，即靶蛋白氨基酸序列中的相應(yīng)同源氨基酸替換。位于非保守區(qū)域內(nèi)的氨基酸的結(jié)構(gòu)可以通過利用標(biāo)準(zhǔn)肽幾何學(xué)或通過分子模擬技術(shù),諸如分子動(dòng)力學(xué)手工比對(duì)。該過程中最后的步驟可以通過利用分子動(dòng)力學(xué)和/或能量最小化精修整個(gè)結(jié)構(gòu)來完成。如此同源建模是本領(lǐng)域中技術(shù)人員公知的技術(shù)(參見，例如Greer,Science(科學(xué))，卷228,(1.985),1055,和Blundell等，Eur.J.Biochem(歐洲生物化學(xué)雜志)，卷172，(1988),513)。這些參考文獻(xiàn)中描述的技術(shù)，以及本領(lǐng)域中通常可獲得的其他同源建模技術(shù)可以用于執(zhí)行本發(fā)明。因此，本發(fā)明的另一方面提供預(yù)測(cè)靶LTC4S蛋白或其他MAPEG家族成員蛋白或其(靶蛋白)同源或異源多聚體的三維結(jié)構(gòu)的方法，所述方法包括以下步驟比對(duì)靶蛋白氨基酸序列的表示和任選地以不大于2.0A,優(yōu)選小于1.5A,1.0，o.5A的均方根偏差變化的表丨或II的LTC4S氨基酸序列，或其選定的坐標(biāo),從而使氨基酸序列的同源區(qū)匹配；關(guān)于如表I或II所定義的LTC4S結(jié)構(gòu)的相應(yīng)區(qū)域?qū)λ霭械鞍椎钠ヅ渫磪^(qū)的結(jié)構(gòu)建模，任選地以不大于2，1.5或IA的均方根偏差變化，或其選定的坐標(biāo)；和確定所述靶蛋白的構(gòu)象，其基本保持所述匹配的同源區(qū)的結(jié)構(gòu)。優(yōu)選的方法利用計(jì)算機(jī)建模進(jìn)行。MAPEG家族成員可以是FLAP,MGSTl，MGST2,MGST3,MPGES-I或LTC4S蛋白。典型地，MAPEG家族成員的結(jié)構(gòu)可以是未知的或僅以低分辨率，例如，以小于2.5A的分辨率已知。預(yù)測(cè)的結(jié)構(gòu)可以,例如，是關(guān)于LTC4S多肽和FLAP多肽的異源多聚體(異源二聚體)，或其中LTCS的內(nèi)部片斷被FLAP的相應(yīng)片斷替換的融合物預(yù)測(cè)的結(jié)構(gòu),如上所示。本發(fā)明的另一方面提供獲得靶LTC4S蛋白或其他MAPEG家族成員蛋白或其(靶蛋白)同源或異源多聚體結(jié)構(gòu)的方法,所述方法包括以下步驟提供所述靶蛋白的晶體；獲得所述晶體的X射線衍射圖；通過對(duì)表I或II的LTC4S結(jié)構(gòu)士自蛋白質(zhì)主鏈原子的小于2.0A,優(yōu)選小于1.5A,1.0,或0.5A的均方根偏差，或其選定的坐標(biāo)對(duì)所述靶蛋白的結(jié)構(gòu)進(jìn)行建模,來計(jì)算所述靶蛋白三維原子坐標(biāo)結(jié)構(gòu)。因此，所述LTC4S結(jié)構(gòu)可以有效用于解釋來自相關(guān)多肽的X射線衍射數(shù)據(jù)。在本發(fā)明的另一方面，LTC4S的3D結(jié)構(gòu)，如本文中提供地，可以用于解釋電子結(jié)晶數(shù)據(jù),從而由2D晶體產(chǎn)生結(jié)構(gòu)。因此,本發(fā)明的另一方面提供獲得靶LTC4S蛋白或其他MAPEG家族成員蛋白或其(靶蛋白)同源或異源多聚體結(jié)構(gòu)的方法,所述方法包括以下步驟提供所述靶蛋白的晶體；獲得所述晶體的X射線衍射圖；通過關(guān)于表I或II的LTC4S結(jié)構(gòu)士自蛋白質(zhì)主鏈原子的小于2.0A，優(yōu)選小于1.5A,1.0,或0.5A的均方根偏差，或其選定的坐標(biāo)對(duì)所述靶蛋白的結(jié)構(gòu)進(jìn)行建模，計(jì)算所述靶蛋白三維原子坐標(biāo)結(jié)構(gòu)。所述晶體可以是2D晶體。本發(fā)明的另一方面提供用于選擇或設(shè)計(jì)預(yù)期用于調(diào)節(jié)MAPEG家族成員蛋白或其同源或異源多聚體活性的化合物的方法,所述方法包括下述步驟使用分子建模方式選擇或設(shè)計(jì)預(yù)期與MAPEG家族成員蛋白或其同源或異源多聚體的催化位點(diǎn)或底物結(jié)合區(qū)相互作用的化合物，其中MAPEG家族成員蛋白或其同源或異源多聚體的催化位點(diǎn)或底物結(jié)合區(qū)的至少一部分的三維結(jié)構(gòu)與化合物的三維結(jié)構(gòu)比較，和選擇預(yù)期與所述催化位點(diǎn)或底物結(jié)合區(qū)相互作用的化合物,其中MAPEG蛋白或其復(fù)合物的催化位點(diǎn)或底物結(jié)合區(qū)的至少一部分的三維結(jié)構(gòu)是通過按照本發(fā)明前述三方面的方法預(yù)期或獲得的三維結(jié)構(gòu)(或其部分)。在本發(fā)明用于選擇或設(shè)計(jì)化合物的方法中，待擬合的分子結(jié)構(gòu)可以采用藥效團(tuán)模型的形式。本發(fā)明的另--方面提供基于計(jì)算機(jī)的合理藥物設(shè)計(jì)方法,包括(a)提供如表I或II定義的LTC4S結(jié)構(gòu)的坐標(biāo)，其任選地以小于2.0，1.5，1.0或0.5A的蛋白質(zhì)主鏈原子均方根偏差變化，或其選定的坐標(biāo)；(b)提供許多分子片段的結(jié)構(gòu)；(c)使各種分子片段的結(jié)構(gòu)擬合選定的坐標(biāo)；和(d)將所述分子片段裝配為單分子以形成候選調(diào)節(jié)分子。所述方法可以進(jìn)一步包括以下步驟(a)獲得或合成分子片段或調(diào)節(jié)分子；和(b)使所述分子片段或調(diào)節(jié)分子與LTC4S相接觸以確定所述分子片段或調(diào)節(jié)分子與LTC4S相互作用的能力。選定的坐標(biāo)可以是定義活性位點(diǎn)，例如底物結(jié)合區(qū)或催化位點(diǎn)的坐標(biāo),如上討論地。片段可以,例如,擬合于活性位點(diǎn)的不同部分并可以利用本領(lǐng)域中技術(shù)人員公知的技術(shù)裝配在一起。參見，例如，Hajduk&Greer(2007)NatureReviewsDrugDiscovery(自然藥物發(fā)現(xiàn)綜述)6，211-219。本發(fā)明的另一方面提供獲得LTC4S三維結(jié)構(gòu)表示的方法,所述方法包括提供表I或II:的數(shù)據(jù),其任選以小于2.0,1.5,1.0或0.5A的蛋白質(zhì)主鏈原子均方根偏差變化，或其選定的坐標(biāo),和構(gòu)建表示所述坐標(biāo)的三維結(jié)構(gòu)。所述結(jié)構(gòu)可以表示為，例如，(a)網(wǎng)架模型；(b)網(wǎng)狀模型；(C)球_棒狀模型；(d)空間填充模型；(e)棒狀模型；(f)帶狀模型；(g)蛇形模型；(h)箭-圓柱模型；(i)電子密度圖；(j)分子表面模型。本發(fā)明的另--方面提供計(jì)算機(jī)可讀存儲(chǔ)介質(zhì)或計(jì)算機(jī)系統(tǒng),其意欲產(chǎn)生化合物的結(jié)構(gòu)和/或進(jìn)行最優(yōu)化，所述化合物與LTC4S或其他MAPEG家族成員蛋白或其同源或異源多聚體，LTC4S或其他MAPEG家族成員蛋白或其同源或異源多聚體與化合物的復(fù)合物相互作用，所述存儲(chǔ)介質(zhì)或系統(tǒng)包含計(jì)算機(jī)可讀數(shù)據(jù)，其包括以下各項(xiàng)中的一種或多種(a)表I或II的LTC4S坐標(biāo)數(shù)據(jù)，其任選地以小于2.0,1.5,1.0或0.5A的蛋白質(zhì)主鏈原子均方根偏差變化，或其選定的坐標(biāo)；所述數(shù)據(jù)定義LTC4S或其選定的坐標(biāo)的三維結(jié)構(gòu)；(b)靶MAPEG家族成員蛋白或其同源或異源多聚體的原子坐標(biāo)數(shù)據(jù)，其通過基于任選地以小于2.0,1.5,1.0或0.5A的蛋白質(zhì)主鏈原子均方根偏差變化的表I或Π的坐標(biāo)數(shù)據(jù),或其選定的坐標(biāo)對(duì)靶標(biāo)同源建模產(chǎn)生；(c)靶MAPEG家族成員蛋白或其同源或異源多聚體的原子坐標(biāo)數(shù)據(jù)，其通過基于參考表I或II的坐標(biāo)數(shù)據(jù),其任選地以小于2.0,1.5,1.O或0.5A的蛋白質(zhì)主鏈原子均方根偏差變化，或其選定的坐標(biāo)解釋X射線晶體數(shù)據(jù)或NMR數(shù)據(jù)產(chǎn)生；(d)可來源于(b)或(c)的原子坐標(biāo)數(shù)據(jù)的結(jié)構(gòu)因子數(shù)據(jù)；和(e)表I或II的原子坐標(biāo)數(shù)據(jù),其任選地以小于2.0，1.5，1.0或0.5A的蛋白質(zhì)主鏈原子均方根偏差變化,或其選定的坐標(biāo)。所述計(jì)算機(jī)系統(tǒng)可以有效用于執(zhí)行本發(fā)明的選擇或設(shè)計(jì)方法。術(shù)語“計(jì)算機(jī)可讀存儲(chǔ)介質(zhì)”應(yīng)該是本領(lǐng)域中技術(shù)人員公知的,且包括可以通過計(jì)算機(jī)閱讀和直接訪問的任何一種或多種介質(zhì)。所述介質(zhì)包括，但不僅限于磁性存儲(chǔ)介質(zhì)諸如軟盤，硬盤存儲(chǔ)介質(zhì)和磁帶；光學(xué)存儲(chǔ)介質(zhì)諸如光盤或CD-ROM；電存儲(chǔ)介質(zhì)諸如MM和ROM；和這些種類的混合諸如磁性/光學(xué)存儲(chǔ)介質(zhì)。術(shù)語“計(jì)算機(jī)系統(tǒng)”也應(yīng)該是本領(lǐng)域中技術(shù)人員公知的，且包括用于分析本發(fā)明的原子坐標(biāo)數(shù)據(jù)的硬件工具、軟件工具和數(shù)據(jù)存儲(chǔ)工具。本發(fā)明的基于計(jì)算機(jī)的系統(tǒng)的最少硬件工具典型地包括中央處理器(CPU)、工作存儲(chǔ)器和數(shù)據(jù)存儲(chǔ)工具，和例如，輸入工具，輸出工具等。還可以提供監(jiān)測(cè)器以顯現(xiàn)結(jié)構(gòu)數(shù)據(jù)。所述數(shù)據(jù)存儲(chǔ)工具可以是RAM或用于訪問本發(fā)明的計(jì)算機(jī)可讀介質(zhì)的工具。所述系統(tǒng)的實(shí)例是可獲自Silicon(iraphicslncorporated(硅制圖公司)的微型計(jì)算機(jī)工作站和運(yùn)行基于Unix，基于Linux，WindowsNT或IBMOS/2操作系統(tǒng)的SunMicrosystems(陽光微型系統(tǒng))。應(yīng)該理解本發(fā)明的方法可以通過遠(yuǎn)程訪問本發(fā)明的原子坐標(biāo)數(shù)據(jù),例如使用因特網(wǎng)執(zhí)行。本文中參考的所有文獻(xiàn)通過參考在此引入?，F(xiàn)通過參考以下非限制性附圖和實(shí)施例更加詳細(xì)地描述本發(fā)明。以下和本說明書中以前給出的全部參考文獻(xiàn)通過參考在此弓I入本文。圖1白三烯生物合成中的關(guān)鍵酶和中間產(chǎn)物。圖21^(；合酶的全結(jié)構(gòu)。a)左側(cè),采用帶狀結(jié)構(gòu)表示的LTC4合酶原聚體的正視圖，其顯示螺旋1-5。整個(gè)LTC4合酶多肽，除最后的殘基(GSH-復(fù)合結(jié)構(gòu)中的最后4個(gè))外，可以在電子密度圖中示蹤。右側(cè)，同源三聚體。結(jié)合的谷胱甘肽，表示活性位點(diǎn)的位置,采用球和棒狀表示法。近似的膜位置通過黑線表示。b)該三聚體的胞質(zhì)視圖，其顯示具有覆蓋各個(gè)結(jié)合袋的環(huán)1的三個(gè)活性位點(diǎn)的位置。以球棒狀表示法顯示的谷胱甘肽與建模去污劑一起。圖3底物和脂質(zhì)蛋白相互作用。a)三聚體蛋白的表面表示法。存在內(nèi)襯蛋白質(zhì)表面的碳鏈球棒狀表示。顯示去污劑分子并在其下粗略觀察到結(jié)合的谷胱甘肽。b)來自如a)中所示的LTC4合酶胞質(zhì)側(cè)的橫截面,其揭示GSH的極性結(jié)合袋和其中結(jié)合脂肪族共底物的裂隙。虛線鍵突出去污劑分子的第二吡喃糖苷的部分占據(jù)。圖4谷胱甘肽結(jié)合。a)以球棒狀表示法顯示的結(jié)合的谷胱甘肽的電子密度圖QFtrFe,在精修前以3σ表示輪廓并用apo結(jié)構(gòu)定相)。相應(yīng)地標(biāo)記相互作用側(cè)鏈。與谷胱甘肽的化學(xué)鍵繪制為虛線。配位的水分子顯示為球體。b)apo-和谷胱甘肽結(jié)合結(jié)構(gòu)中活性位點(diǎn)的重疊。谷胱甘肽以棒狀表示法顯示且顯示來自apo-結(jié)構(gòu)的硫酸鹽分子。圖5疏水性結(jié)合裂隙和提議的底物結(jié)合和催化示意性機(jī)制。a)以顯示為棒狀的相互作用和邊界殘基顯示的2個(gè)單體之間的界面。球體顯示半胱氨酰基硫所在的區(qū)域。結(jié)合的去污劑以球棒模型圖示。b)相對(duì)于a)逆時(shí)針方向旋轉(zhuǎn)90°的底物結(jié)合區(qū)的側(cè)視圖。為了清楚，僅圖示了具有Trpll6’裂隙的單體。去除的單體為脂質(zhì)結(jié)合裂隙貢獻(xiàn)疏水性殘基和為谷胱甘肽貢獻(xiàn)極性殘基。C)提議的底物結(jié)合和綴合的示意圖。圖6MAPEG家族的序列比對(duì)。人(h)LTC4S的初級(jí)序列與來自小鼠(m)、大鼠(r)、牛(c)和雞(ch)的其他MAPEG成員進(jìn)行比對(duì)。大寫的G表示結(jié)構(gòu)中結(jié)合GSII的殘基。突出這些殘基的保守性。螺旋以相應(yīng)的螺旋編號(hào)顯示。圖7由LTC4合酶催化的反應(yīng)的示意圖。左側(cè)的UTA4和谷胱甘肽在不可逆的反應(yīng)中綴合形成LTC4。圖8金屬配位和晶體包裝a)核周圖，其通過六組氨酸標(biāo)記物顯示一種單金屬三聚體的完全配位和3種金屬(點(diǎn))的部分配位。b)晶體對(duì)稱,很大程度上受如a)中所示配位N-末端的總共8種金屬/十二聚體(dodecamer)的金屬團(tuán)的控制。圖9谷胱甘肽結(jié)合活性位點(diǎn)的立體圖，其顯示關(guān)于以棒球表示法顯示的結(jié)合的谷胱甘肽的電子密度(2F0-FC,在精修前以3σ表示輪廓并用apo結(jié)構(gòu)定相)。相互作用側(cè)鏈,相應(yīng)由單體染色和標(biāo)記。與谷胱甘肽的化學(xué)鍵繪制為虛線。圖10蛋白質(zhì)配體相互作用的示意圖。谷胱甘肽和相互作用殘基的ligplot，其以虛線顯示鍵長(zhǎng)度和相互作用。黑色虛線表示Argl04'和半胱氨?；蛑g的相互作用。實(shí)施例1關(guān)于LTC4S的結(jié)晶和結(jié)構(gòu)確定材料和方法咪唑，Tris堿，NaCl，KCl,TritonΧ-100,脫氧膽酸鈉，S-己基谷胱甘肽瓊脂糖，4_(二丙基氨磺?；?苯甲酸,還原性谷胱甘肽(GSH),和2-巰基乙醇獲自Sigma(西格瑪)。十二烷基麥芽糖苷獲自Anatrace。人LTC4S作為六組氨酸構(gòu)建體表達(dá)在酵母中。利用TritonX-100和Triton-DOC混合物進(jìn)行從膜提取。蛋白質(zhì)利用兩個(gè)親合層析法步驟純化并以凝膠過濾結(jié)束，從而容許去污劑交換為正-卜二烷基βH〕-麥芽糖苷?？寺『唾|(zhì)粒構(gòu)建將人LTC4ScDNA(I.Μ.A.G.Ε.cDNA克隆5277851，MRCgeneservice(MRC基因月艮務(wù))，劍橋，英國(guó))亞克隆到pPICZA(Invitrogen)中。增補(bǔ)編碼His6標(biāo)記物的N末端序列的cDNA和載體均進(jìn)行PCR擴(kuò)增，并將產(chǎn)物共轉(zhuǎn)化為CaC:[2感受態(tài)的大腸桿菌(E.coli)(T0P10,Iiwitrogen),利用大腸桿菌的內(nèi)源重組酶活性重組片段。編碼由此產(chǎn)生的質(zhì)粒pPICZ-hisLTC4S的一部分的蛋白通過DNA測(cè)序驗(yàn)證。蛋白質(zhì)表達(dá)和純化利用PichiaEasyComp轉(zhuǎn)化試劑盒(Invitrogen)將表達(dá)載體轉(zhuǎn)化到巴斯德畢赤酵母(P.pastoris)KM71H細(xì)胞中。將重組細(xì)胞在帶有隔板的燒瓶中2.5L具有甘油的最小酵母培養(yǎng)基(Invitrogen)中27°C培養(yǎng)。當(dāng)0D600達(dá)到8_10時(shí)，將細(xì)胞重新混懸在0.5L具有0.5%甲醇的最小酵母培養(yǎng)基中。72h后通過離心(2500xg,7min)捕獲細(xì)胞并重新混懸在50mMTris-HCLpH7.8,IOOmMKCl和10%甘油中。用玻璃珠(0.5mra)對(duì)細(xì)胞勻漿并使?jié){液通過尼龍網(wǎng)濾器(180μm,Millipore)過濾并離心(1500xg,IOmin)。用TritonX-100(1%,ν/ν)和脫氧膽酸鈉(0.5%,w/v)在冰上攪拌lh，來溶解上清液中的膜結(jié)合蛋白。離心(10OOOxg,IOmin)后，對(duì)上清液增補(bǔ)IOmM咪唑并加載到Ni-瓊脂糖快流(GEHealthcare(GE衛(wèi)生保健))上。用增補(bǔ)了20mM咪唑和0.IMNaCl的緩沖液A(25mMTris-HCLpH7.8,10%甘油，0.1%TritonX-100和5mM2-巰基乙醇)清洗柱，隨后另外用含有40mM咪唑和0.5MNaCl的緩沖液A清洗。用在緩沖液A中的300mM咪唑，0.5MNaCl和0.ImMGSH將LTC4合酶洗脫。純化的最終步驟在裝有3mLS-己基谷胱甘肽瓊脂糖的柱上進(jìn)行。用增補(bǔ)了0.5MNaCl和0.ImMGSH的緩沖液A清洗該柱。純化的LTC4合酶用25mMTris-HCl,pH7.8,0.1%TritonX-100，30mM4_(二丙基氨磺?；?苯甲酸，5mM2-巰基乙醇和0.ImMGSH洗脫。將純化的蛋白質(zhì)冷凍保存在20oC或在Superdex20016/60(GEHealthcare(GE衛(wèi)生保健))上在緩沖液交換步驟中直接進(jìn)一步修飾(polished),所述Superdex20016/60用0.03%W/'νDDM(w/v),20mMTrispH8.0,300mMNaCl和0,5mMTCEP平衡。通過超濾將包含LTC4合酶的餾分濃縮到3.Imgml_l。結(jié)晶利用沉滴蒸汽擴(kuò)散技術(shù)(sittingdropvapourdiffusiontechnique)，使晶體在4°C或20°C,從3.ImgπιΓ1的膜蛋白溶液開始生長(zhǎng)。晶體典型地在3_4天后出現(xiàn),約7天后達(dá)到最佳尺寸。將含有20mMTrispH8.0,300mMNaCl，0.03%(w/v)DDM的蛋白溶液，與含有200raMNaCl,IOOmM二甲胂酸鈉pH6.5，2M:硫酸銨(AmSO4)的儲(chǔ)液(對(duì)于天然蛋白)；與含有2%PEG400,IOOmMHEPESNapH7.5,2MAmS04的儲(chǔ)液(對(duì)于GSH衍生物)或與含有IOOmMbis-TrisΡΗ5·5，2ΜAmS04的儲(chǔ)液(對(duì)于重原子摻入物(soak))混合(1:1)。對(duì)于后者，使晶體在20°C生長(zhǎng)并在溶于人工母液中的2，5mMPtCN4中浸泡2小時(shí)。GSH衍生物通過混合等體積的溶于母液的6m:M:GSH和蛋白質(zhì)混合，并在4°C保持浸泡24小時(shí)來獲得。將所有晶體轉(zhuǎn)移到它們用于低溫保護(hù)增補(bǔ)了25%甘油的相應(yīng)儲(chǔ)液中，然后在液氮中速凍。全部X射線數(shù)據(jù)在歐洲同步加速器輻射機(jī)構(gòu)(EuropeanSynchrotronRadiationFacility)(ESRF)中在波束線ID14-4和ID23-2上收集。利用MosfIm和SCALA處理和測(cè)量天然和GSH浸泡的晶體的衍射數(shù)據(jù)，而XDS組用于處理和測(cè)量重原子MAD數(shù)據(jù)組。關(guān)于3.2A的三個(gè)高度冗余的數(shù)據(jù)組在基于由晶體收集的χ射線熒光光譜的PtLIII邊緣周圍收集。單怕位點(diǎn)在以XPREP局部測(cè)量后,利用SIIELXD，基于峰數(shù)據(jù)組中觀察到的反常差異定位,并且SHELXE28證實(shí)正確的影響(hand)。利用程序SHARP29獲得良好的實(shí)驗(yàn)MAD(多波長(zhǎng)反常衍射)相，由此分別關(guān)于無中心/中心反射產(chǎn)生0.41/0.26的總品質(zhì)因數(shù)(FOM)。利用SOLOMON3ci中75%的溶劑含量進(jìn)一步改進(jìn)這些相，由此產(chǎn)生0.88的總品質(zhì)因數(shù)。最初的圖譜用于建模α-螺旋,其隨即與高分辨率數(shù)據(jù)一起使用，從而以ARP/WARP31分配殘基,設(shè)法使其構(gòu)建80%的序列。該模型進(jìn)一步利用Coot32構(gòu)建,并用于使用較高分辨率apo結(jié)構(gòu)和GSH結(jié)合結(jié)構(gòu)的移相器(Phaster)33的分子替換。這兩種蛋白質(zhì)模型均以Coot構(gòu)建并利用Refmac34對(duì)apo模型精修到R工作/R_為17.6/21.2%和對(duì)GSII結(jié)合結(jié)構(gòu)精修到18.3/22.0%。所有晶體都屬于空間群F23,其具有約a=b=c=170A和α=β=Y=90°的晶胞尺寸，含有一種單體/具有80%的溶劑含量的不對(duì)稱單元。利用Pymol35制成除圖10以外的所有圖像，圖10使用LIGPL0T36形成。表8.數(shù)據(jù)收集、定相和精修統(tǒng)計(jì)學(xué)。<table>tableseeoriginaldocumentpage35</column></row><table>結(jié)果和討論LTC4結(jié)構(gòu)和膜相互作用我們已經(jīng)確定了采用其apo和GSH-復(fù)合形式的人LTC4合酶的晶體結(jié)構(gòu)，分別達(dá)到分辨率2.0和2.15A。完整的LTC4S多肽,除最后的殘基(GSH-復(fù)合結(jié)構(gòu)的最后四個(gè))外，可以在電子密度圖中示蹤。另外，用于純化的N末端6-His標(biāo)記物清晰可見，且形成獨(dú)特的金屬配體團(tuán)，其包括12個(gè)晶體相關(guān)六組氨酸標(biāo)記物(圖8)，其配位8個(gè)金屬。許多擴(kuò)展的密度，其可能源自購買的去污劑或脂質(zhì),可以在圖譜中觀察到,并已作為用于純化的去污劑十二烷基麥芽糖苷(DDM)或作為試驗(yàn)性脂肪族鏈引入到晶體精修中。所述脂肪族鏈的值得注意的團(tuán)針對(duì)螺旋1、3和5包裝，強(qiáng)調(diào)螺旋5的高度疏水性，其中前一半幾乎排他地包括疏水性殘基(圖3a)。在其天然膜環(huán)境中,似乎可能的是,螺旋5稍微改變方向，從而作為界面表面螺旋包埋在脂雙層中。LTC4S包括5個(gè)長(zhǎng)α-螺旋-前面的4個(gè)(螺旋1-4)形成跨膜片斷，而螺旋5延伸出膜平面(圖2)。晶體結(jié)構(gòu)揭示緊湊的三聚體蛋白，其中三倍晶軸使三個(gè)亞基相關(guān)聯(lián)。三個(gè)TM螺旋連接環(huán)中的兩個(gè)是短的(環(huán)2和3)，而環(huán)1,其連接螺旋1和2,較長(zhǎng)，由11個(gè)殘基構(gòu)成。環(huán)1在相鄰單體的頂部上折疊并在三聚體中有助于亞基相互作用(圖2)。螺旋4和5通過短的含脯氨酸的轉(zhuǎn)角相連，且螺旋5還可以被看做是螺旋4的延長(zhǎng)。通過結(jié)合的GSH確定的LTC4S活性位點(diǎn)埋藏在兩個(gè)鄰近的靠近膜表面的單體之間的界面處，環(huán)1位于其中?？赡艿?蛋白質(zhì)的這部分面對(duì)外部核膜的胞質(zhì)側(cè)。這應(yīng)該促進(jìn)底物和產(chǎn)物的遞送和釋放，因?yàn)楹铣赏緩街械那笆龊鸵訤步驟在膜的胞質(zhì)側(cè)進(jìn)行。晶體接觸通過C末端螺旋,蛋白核周側(cè)上的N末端6-IIis標(biāo)記物和還通過胞質(zhì)側(cè)上的環(huán)1和3介導(dǎo)。晶體僅含有20%的蛋白，但仍衍射到達(dá)高分辨率的事實(shí)是不尋常的,但是可以通過高度對(duì)稱的空間群(F23)和令人感興趣的包含內(nèi)部晶體322對(duì)稱性的6-His多核金屬團(tuán)來解釋(圖8)。電子密度圖揭示許多擴(kuò)展的電子密度，其可能源自結(jié)合的去污劑和脂質(zhì)分子(圖2a)。在GSH摻入的結(jié)構(gòu)中，一種試驗(yàn)性DDM分子靠近結(jié)合的GSH建模,從而在來自一個(gè)亞基的螺旋1和來自相鄰亞基的螺旋3之間形成的裂隙中產(chǎn)生活性位點(diǎn)(見下)。在apo-LTC4S結(jié)構(gòu)中，2種DDM分子在該區(qū)域內(nèi)建模。大多數(shù)另外的脂肪族鏈也在TM區(qū)的核周部分上觀察到，且包括存在于三聚體中心的一個(gè)延長(zhǎng)的鏈,其對(duì)穩(wěn)定三聚體結(jié)構(gòu)可能是重要的。一般,包含活性位點(diǎn)袋的分子的胞質(zhì)部分是更加極性的?；钚晕稽c(diǎn)在酶的胞質(zhì)部分上的位置與存在于胞質(zhì)中的5-L0,即產(chǎn)生LTC4S的共底物的酶的位置一致。拓?fù)溥€與胞質(zhì)中存在已知磷酸化LTC4S的S28的蛋白激酶C(GuptaN等FEBSLett.(FEBS書信)(1999)449(1):66-70)相一致。LTA4S的四-螺旋TM拓?fù)溥€受到LTC4S的低分辨率電子衍射投影圖的支持(Schmidt-Krey等,2004,見上)。四螺旋TM結(jié)構(gòu)也在遙遠(yuǎn)相關(guān)的MGSTl的低分辨率電子晶體結(jié)構(gòu)中觀察到(Holm等2006，見上)?；钚晕稽c(diǎn)結(jié)構(gòu)和底物結(jié)合LTC4合酶的活性位點(diǎn)的位置由清楚結(jié)合的GSH揭示。該酶的活性位點(diǎn)埋藏在靠近膜表面的2個(gè)鄰近的單體的界面處,環(huán)1位于其中,在來自一個(gè)單體的螺旋1和2和來自相鄰單體的3和4之間。可能地，蛋白的這個(gè)部分面對(duì)外部核膜的胞質(zhì)側(cè)。這應(yīng)該促進(jìn)底物和產(chǎn)物的遞送和釋放，因?yàn)楹铣赏緩街械那笆龊鸵韵虏襟E在膜的胞質(zhì)側(cè)進(jìn)行。GSII采用馬蹄形構(gòu)象,位于來自一個(gè)單體的螺旋1和2和來自相鄰單體的3和4之間的界面處的極性袋的深處(圖2b,3b)。GSH的羧酸鹽部分面對(duì)蛋白基質(zhì),而硫醇基團(tuán)針對(duì)其中結(jié)合DDM分子的膜層(圖2b)。極性相互作用由GSH通過來自構(gòu)成活性位點(diǎn)的兩個(gè)亞基的殘基形成(圖4a、b)。ArgS1'和Arg30在結(jié)合袋的底部,為GSH的兩個(gè)羧酸鹽制備鹽橋,其有效彎曲GSH并將其硫醇基團(tuán)指引到其與Arg104'相互作用并靠近結(jié)合的DDM分子定位的膜界面(圖3b,4a)。與GSH的另外的極性相互作用通過Gln53,Asn55’，Glu58，’Tyr59，，Tyr93，和Tyr97，形成。還形成若千非極性相互作用(He27,Pro37,Leu108，)，從而為GSH進(jìn)入其結(jié)合袋提供良好的擬合。為了詳細(xì)綜述GSH結(jié)合，參見圖10。還以無GSHapo形式確定LTC4S的結(jié)構(gòu),其中試驗(yàn)性硫酸根離子存在于GSH袋中。GSH結(jié)合的LTC4S的結(jié)構(gòu)和apo-LTC4S結(jié)構(gòu)的比較揭示只有極性氨基酸側(cè)鏈的局部調(diào)節(jié)在GSH結(jié)合時(shí)形成(圖4b)。盡管提供與GSII相互作用的疏水性和芳香族殘基在兩種結(jié)構(gòu)中位于非常類似的位置,但是大部分極性殘基在GSH結(jié)合時(shí)改變構(gòu)象。環(huán)1似乎至少部分覆蓋GSH接近其結(jié)合袋(圖2b，4b)。因此,在反應(yīng)周期過程中可能需要--些環(huán)1的柔性,這與該環(huán)在GSH結(jié)合時(shí)的結(jié)構(gòu)重排相一致(圖4)。識(shí)別親脂性LTA4底物與親脂性底物復(fù)合的酶的結(jié)構(gòu)很稀少并且實(shí)際上，除電子載體外,在關(guān)于與其脂質(zhì)底物或其良好類似物的復(fù)合的膜內(nèi)在酶的文獻(xiàn)中不能獲得直接的結(jié)構(gòu)信息(http://bianco,biomol.uci.edu/Membrane_Proteins_xtal.html)。LTC4SLTA4^tij#學(xué)研究是有挑戰(zhàn)的，這歸因于這種包含環(huán)氧化物的化合物的短壽命(10秒)。然而，在GSH復(fù)合的LTC4S結(jié)構(gòu)中，親脂性分子已經(jīng)在活性位點(diǎn)區(qū)內(nèi)結(jié)合,并且基于脂肪族鏈的長(zhǎng)度和其頭部基團(tuán)的表觀結(jié)構(gòu)，該分子被確定為DDM,盡管末端糖基主要是混亂的(圖4a)。然而，12-碳鏈和第一糖基以電子密度充分定義，且我們提議該結(jié)合的去污劑可以起LTA4與酶的結(jié)合的良好模型的作用，因?yàn)槠渚哂信cLTA4的重要結(jié)構(gòu)相似性。脂肪族鏈在酶脂質(zhì)界面上的延長(zhǎng)的腔中結(jié)合，并且該親脂性化合物的結(jié)合模型定位原子15,由位于GSH硫醇基團(tuán)頂部上的ω-末端開始計(jì)數(shù),這與LTA4在該位置,LTA4底物的C6與GSH綴合相--致。提議的LTA4的結(jié)合谷因此由狹窄的延長(zhǎng)裂隙構(gòu)成，所述裂隙由疏水性殘基形成(圖4a)。去污劑的疏水性尾部由來自一個(gè)亞基的Ala20,Leu24,Ile27和來自相鄰亞基的Tyr59，，Trp116'，Ala112',Leu115，，Leul08，和Tyr109，排列而成。Trpl16，在其在底物的ω-末端上形成蓋子時(shí)，起定位脂肪族鏈的關(guān)鍵作用。Trpll6’袋構(gòu)成用于固定脂質(zhì)ω-末端位置的獨(dú)創(chuàng)性模型，其有效地起標(biāo)尺的作用，從而容許LTA4的C6在GSH硫醇中的適當(dāng)定位。在無GSH的apo-LTC4S結(jié)構(gòu)中，DDM分子也在蛋白的這個(gè)區(qū)域內(nèi)結(jié)合，但是與GSH復(fù)合的結(jié)構(gòu)中的DDM相比，去污劑分子進(jìn)一步轉(zhuǎn)化為脂雙層(圖5b)。該轉(zhuǎn)化的作用是與LTA4的C6相應(yīng)的去污劑原子的位置現(xiàn)在被發(fā)現(xiàn)距GSH硫醇在GSH結(jié)構(gòu)中所在位置處超過8A。此外，apo-LTC4S結(jié)構(gòu)中的去污劑沒有以其ω-端楔入Trp116袋,但是該端改為位于袋外。這為這樣的事實(shí)提供進(jìn)--步的支持，所述事實(shí)是Trp116在比對(duì)LTC4S的活性位點(diǎn)中LTA4的脂肪族鏈中起重要作用。還提示，GSH結(jié)合協(xié)助形成合適的脂質(zhì)結(jié)合裂隙，這大概是通過覆蓋活性位點(diǎn)中的帶電基團(tuán)和擴(kuò)展脂質(zhì)的相互作用表面，從而容許LTA4進(jìn)入LTC4S活性位點(diǎn)中的生產(chǎn)性結(jié)合模式。為了促進(jìn)GSH綴合反應(yīng)，GSH硫醇的親核性最可能通過酶增強(qiáng)。Arg104理想定位，從而促進(jìn)GSH硫醇通過其帶正電引起的pKa改變，其中η-氮之一能夠介導(dǎo)與GSH硫的極性相互作用(3.2Α)。該異常短的硫_氮距離以及另外的氫鍵受體的缺少提示酶結(jié)合的硫醇基團(tuán)實(shí)際上可以處于晶體結(jié)構(gòu)的陰離子硫醇鹽，如關(guān)于疏遠(yuǎn)相關(guān)的MGST-I23所提示地。GSH硫醇充分定位，以親核攻擊LTA437的環(huán)氧乙烷環(huán)的烯丙位C6。不存在位于活性位點(diǎn)中的明顯酸性殘基，所述活性位點(diǎn)提供質(zhì)子，以演化底物的C-O基團(tuán)。因此可能地，通過與酶的氫鍵鍵合穩(wěn)定底物氧陰離子(oxyanion)。Argl04位于底物C5預(yù)期位置的附近，且因此還可以協(xié)助穩(wěn)定底物陰離子。另外，Arg31位于底物的遠(yuǎn)側(cè)，且即使其在所述結(jié)構(gòu)中是柔性的,但是該殘基還可以協(xié)助穩(wěn)定底物陰離子。由此產(chǎn)生的SN2機(jī)制的手性通過活性位點(diǎn)中環(huán)氧化物的生產(chǎn)性結(jié)合來定義。在該反應(yīng)中,環(huán)氧化物的開啟將導(dǎo)致手性倒置，從而使得LTA4的環(huán)氧化物氧的6S立體化學(xué)應(yīng)該被完全轉(zhuǎn)變?yōu)橛纱水a(chǎn)生的產(chǎn)物L(fēng)TC4的谷胱甘肽基部分的6R構(gòu)型。圖5c描述了關(guān)于底物結(jié)合和LTC4合酶產(chǎn)物產(chǎn)生提議的機(jī)制的示意性概述。在提議的結(jié)合方案中，GSH由胞質(zhì)進(jìn)入其結(jié)合袋并通過該行為容許結(jié)合以前位于脂質(zhì)膜中的LTA4。對(duì)LTA4的親水性增加容許LTC4在胞質(zhì)中移出，這可能取決于環(huán)1的柔性。關(guān)于LTC4合酶，特別是關(guān)于TM片斷的定位和活性位點(diǎn)殘基的位置的結(jié)構(gòu)信息容許基于結(jié)構(gòu)比對(duì)MAPEG家族(圖6)。以前的序列比對(duì)提示人MAPEG成員的常見進(jìn)化源,其中序列保守性低但在兩種中心TM片斷，即螺旋2和螺旋314中顯著。然而,末端TM片斷，螺旋1和4中的序列具有更大的分歧，且僅能在亞家族內(nèi)觀察到明顯的相似性。在基于結(jié)構(gòu)的比對(duì)中，通過螺旋1的可能的比對(duì)，將進(jìn)一步的保守性添加到MAPEG家族的活性位點(diǎn)區(qū)。前三個(gè)螺旋的比對(duì)強(qiáng)烈支持大多數(shù)GSH配位殘基在所有GSH依賴性MAPEG成員(全部MAPEG成員，除已知FLAP催化GSH依賴性反應(yīng)外)中是保守的。在來自這些螺旋的8種極性殘基配位GSH中，5種在GSH依賴性酶中是完全保守的，而剩F的3種具有主要保守的氨基酸置換。我們的螺旋4的比對(duì)是更具試驗(yàn)性的。Argl04，本文中提議的關(guān)鍵催化殘基與預(yù)測(cè)位于其他GSH依賴性MAPEG成員的螺旋4的N末端中的精氨酸進(jìn)行比對(duì)。該潛在催化Arg在MGST-I(Argl30)中的位置表現(xiàn)出與MGST-I19的低分辨率結(jié)構(gòu)相一致。盡管氨基酸配位GSH在MAPEG家族中是高度保守的，但是排列提議的LTA4結(jié)合裂隙的殘基卻不是。盡管大多數(shù)相應(yīng)的殘基在其他家族中是疏水性的,但是其尺寸和芳香性組成不同。這可以說明MAPEG成員如何演化從而識(shí)別相同袋中的不同脂質(zhì)底物結(jié)合。然而,還可以提示脂質(zhì)識(shí)別在其他家族成員中以不同方式發(fā)生，例如，MGST-I演化為高度非特異性的。另外,LTA4的頭部基團(tuán)的性質(zhì)在不損失酶活性的條件下，顯示出是可變的38,39。這種對(duì)頭部基團(tuán)的主要特異性的缺乏大概可以通過在該區(qū)域內(nèi)更廣范圍來解釋，這不為羧酸鹽提供任何不同的結(jié)合袋(圖3a，5a)?？傊珿SH的馬蹄性結(jié)合模式似乎在全部GSH依賴性MAPEG家族成員中是保守的且，潛在地，GSH活化的結(jié)構(gòu)基礎(chǔ)似乎可以有關(guān)。在LTC4合酶中，位置104處的精氨酸可能起活化GSII硫醇的關(guān)鍵作用，從而親核攻擊LTA4環(huán)氧化物。引起興趣的LTC4合酶脂質(zhì)結(jié)合袋容許LTA4通過Trpl16裂隙擬合活性位點(diǎn)，其有效定位底物的C6,從而與GSH綴合。似乎可能的是,該脂質(zhì)底物識(shí)別原則主要基于脂肪族鏈長(zhǎng)度而非頭部基團(tuán)的性質(zhì)。這可能具有還關(guān)于其他膜內(nèi)在酶中的底物識(shí)別的一些關(guān)系。實(shí)施例2:基于計(jì)算機(jī)的化合物篩選基于結(jié)構(gòu)的藥物設(shè)計(jì)使用已知靶標(biāo)的三維結(jié)構(gòu)作為合理設(shè)計(jì)分子的指導(dǎo),這可以最終引起減輕疾病的試劑,藥物。靶標(biāo)的結(jié)構(gòu)可以通過X射線晶體學(xué)或其他三維結(jié)構(gòu)確定方法獲得。優(yōu)選地，晶體包括靶標(biāo)配體復(fù)合物，其描述相關(guān)結(jié)合模式和推定藥物與靶標(biāo)的理想相互作用。更有利地,制備一系列靶標(biāo)-配體復(fù)合物,其中復(fù)合的配體是一或多系列針對(duì)靶標(biāo)的引導(dǎo)化合物的成員。這還包括設(shè)計(jì)配體，以減少與另--種或多種分子(例如,與靶酶共享底物的另一種酶或多種酶)的結(jié)合，從而改善與一種或多種理想靶標(biāo)的特異性。檢查一種或多種靶標(biāo)配體復(fù)合物的三維結(jié)構(gòu)可以導(dǎo)致提高理解配體的結(jié)合模式和在存在配體條件下靶標(biāo)的結(jié)合腔。該信息可以通過醫(yī)學(xué)化學(xué)或計(jì)算化學(xué)中的一種或多種工具管理，從而形成用于修飾配體的假說，其可以導(dǎo)致結(jié)合親和性的改善或提高有利于作為藥物使用的其他特征?；诮Y(jié)構(gòu)的藥物設(shè)計(jì)的醫(yī)學(xué)化學(xué)和計(jì)算化學(xué)工具包括,但不僅限于,分子建模、實(shí)質(zhì)篩選和對(duì)接、設(shè)計(jì)集中的組合化學(xué)文庫、從頭配體設(shè)計(jì)、用于三維結(jié)構(gòu)確定的另外的候選者的指導(dǎo)、和合理化觀察到的結(jié)構(gòu)_活性關(guān)系。通過應(yīng)用醫(yī)學(xué)和計(jì)算工具指導(dǎo)或啟發(fā)的潛在修飾包括制備配體，以構(gòu)建或調(diào)節(jié)與靶標(biāo)的特異性相互作用，從配體中除去被認(rèn)為不重要或損害與靶標(biāo)理想結(jié)合親和性的基團(tuán)，修飾配體以調(diào)節(jié)針對(duì)其他靶標(biāo)的相對(duì)特異性,和制備配體以在不對(duì)于靶標(biāo)的結(jié)合親和性產(chǎn)生不受歡迎影響的條件下，改進(jìn)其藥物樣特性。在一個(gè)實(shí)例中，在酶活性篩選中被確定具有抑制活性的小分子化合物的結(jié)構(gòu)可以利用Syby!(TriposInc.,1699SouthHanleyRd.,St.Louis,Missouri，63144,美國(guó))分子建模軟件來建模并與使用Coot(Emsley和Cowtan,ActaCrystallographicaD,2004，60，2126-2132)晶體學(xué)建模軟件獲得的該酶活性位點(diǎn)區(qū)內(nèi)相同或相似分子的X射線晶體學(xué)結(jié)構(gòu)進(jìn)行比較?；谠摫容^，可以對(duì)在Sybyl中建模的化合物進(jìn)行改變，其在結(jié)構(gòu)比較的基礎(chǔ)上,被預(yù)期增強(qiáng)或減弱對(duì)酶的抑制。然后可以合成基于這些模型的新的化合物并測(cè)量它們?cè)诿富钚院Y選中的作用。該過程可以重復(fù),例如,在不同輪中，可能集中在所述分子/酶的不同部分或所述化合物的不同特性—I::，如以上討論地。參考文獻(xiàn)1.Saraue1ssοη，B.Leukοtrieηes^Mediatorsofimmediatehypersensitivityreactionsandinflammation(白.三火希速發(fā)超敏反應(yīng)禾口炎的介體).Science(科學(xué))220，568-575(1983).2.Funk,C.D.ProstaglandinsandleukotrienesAdνaηcesineicosanoidbiology(前列腺素和白三烯類花生酸生物學(xué)進(jìn)展).Science(科學(xué))294,1871-1875(2001).3.Samuelsson,B.,Dahlen,S.-Ε.，Lindgren,J.-Α.,Rouzer，C.Α.&Serhan,C.N.Leukotrienesand1ipoxins:Structures,biosynthesis,andbiologicaleffects(白三烯和脂氧素結(jié)構(gòu)、生物合成、和生物學(xué)作用).Science(科學(xué))237,1171-1176(1987).4.Hanna,C.J.，Bach,Μ.K.’Pare,P.D.&Schellenberg,R.R.Slow-ReactingSubstances(Leukotrienes)ContractHuman氣道andPulmonaryVascularSmoothMuscleInvitro(物質(zhì)(白三烯)體外收縮人氣孔和肺血管平滑肌).Nature(自然)290,343-344(1981).5.Dahlen,S.-E.,Hedqvist,P.,Hammarstrom.,S.&Samuelsson,B.Leukotrienesarepotentconstrictorsofhumanbronchi(白三火希是人支氣管的有效收__劑).Nature(自然)288,484~486(1980).6.Dahlen,S.-E.等Leukotrienespromoteplasmaleakageandleukocyteadhesioninpostcapillaryvenules:Invivoeffectswithrelevancetotheacuteinflammatoryresponse(白三烯在毛細(xì)血管后微靜脈中促進(jìn)血漿滲漏和白細(xì)胞粘附關(guān)于急性炎性反應(yīng)的體內(nèi)作用).ProcNatlAcadSciUSA(美國(guó)國(guó)家科學(xué)院學(xué)報(bào))78，3887-3891(1981).7.Weiss,J.W.等BronchoconstrictorEffectsofLeukotriene-CinHumans(白三烯-C在人中的支氣管收縮作用).Science(科學(xué))216,196-198(1982).8.Smedegard,G.等Leukotriene~C4AffectsPulmonaryandCardiovascularDynamicsinMonkey(白三烯在猴中影響肺和心血管動(dòng)力學(xué)).Nature(自然)295，327-329(1982).9.Beller，T.C.等CysteinylIeukotriene1receptorcontrolstheseverityofchronicpulmonaryinflammationandfibrosis(半胱氨?；兹?受體控制慢性肺部炎癥和纖維癥的嚴(yán)重性).Proc.Natl.Acad.Sci.U.S.Α.(美國(guó)國(guó)家科學(xué)院學(xué)報(bào))101，3047-3052(2004)·10.Robbiani,D.F.等TheleukotrieneC4transporterMRPlregulatesCCL19(MIP_3beta,ELC)-dependentmobilizationofdendriticcellstolymphnodes(白三烯C4轉(zhuǎn)運(yùn)蛋白MRPl調(diào)節(jié)CCL19(MIP_3beta，ELC)-依賴性移動(dòng)樹突細(xì)胞到淋巴結(jié)).Cell(細(xì)胞)103，757-68(2000).11.Drazen,J.F.,Israel,Ε.&()‘Byrne,P.Treatmentofasthmawithdrugsmodifyingtheleukotrienepathway(用改善白三烯途徑的藥物治療哮喘).N.Engl..J.Med.(新英格蘭醫(yī)學(xué)雜志)340,197-206(1999).12.Lam,B.K.Musten,K.F.LeukotrieneC-4synthase-.apivotalenzymeincellularbiosynthesisofthecsteinylleukotrienes(白三烯C-4合酶半胱氨酉先基白三烯細(xì)胞生物合成中的關(guān)鍵酶).Prostaglandins&OtherLipidMediators(前列腺素&其他脂質(zhì)介體)68-9，511-520(2002)·13.Penrose,J.F.等PurificationofhumanleukotrieneC—4synthase(A白三烯C4合酶的純化).ProcNat!AcadSciUSA(美國(guó)國(guó)家科學(xué)院學(xué)報(bào))89，11603-11606(1992).14.Nicholson,D.W.等PurificationtohomogeneityandtheN—terminalsequenceofhumanleukotrieneC4synthase:Ahomodimericglutathiones-transferasecomposedof18-kDasubunits)(純化人白三烯C4合酶的同質(zhì)性和N端序列包括18-kDa亞基的同源二聚谷胱甘肽S-轉(zhuǎn)移酶).ProcNatlAcadSciUSA(美國(guó)國(guó)家科學(xué)院學(xué)報(bào))90，2015-2019(1993).15.Lam,B.K.,Penrose,J.F.，F(xiàn)reeman,G.J.Musten,K.F.ExpressioncloningofacDNAforhumanleukotrieneC4synthase,anintegralmembraneproteinconjugatingreducedglutathionetoleukotrieneA4(表達(dá)克隆關(guān)人白ΞΞ；!；希C4合即使還原谷胱甘肽與白三烯A4綴合的膜內(nèi)在蛋白cDNA).Proc.Natl.Acad.Sci.U.S.Α.(美國(guó)國(guó)家科學(xué)院學(xué)報(bào))91,7663-7(1994).16.Welsch,D.J.等MolecularcloningendexpressionofhumanIeukotrieneC4synthase(人白三烯C4合酶的分子克隆末端表達(dá)).Proc.Natl.Acad.Sci.U.S.Α.(美國(guó)國(guó)家科學(xué)院學(xué)報(bào))91，9745-9749(1994).17.Jakobsson,P.J.，Morgenstern,R.，Mancini，J.，F(xiàn)ord-Hutchinson,A.&Persson,B.CommonstructuralfeaturesofMAPEG—awidespreadsuperfamilvofmembraneassociatedproteinswithhighlydivergentfunctionsineicosanoidandglutathionemetabolism(MPEG-在類花生酸和谷胱甘肽代謝中具有高度多樣功能的膜相關(guān)蛋白的普通超家族的共用結(jié)構(gòu)特征).ProteinSci.(蛋白質(zhì)科學(xué))8，689-92.(1999).18.Schmidt-Krev,I.等HumanIeukotrieneC(4)synthaseat4.5AresolutioninProjection(投影中以4.5A分辨率的人白三烯C(4)和酶).Structure(結(jié)構(gòu))12,2009—14(2004).19.Holm,P.J.等Structuralbasisfordetoxificationandoxidativest.ressprotect.ioninmembranes(用于解毒和膜中的氧化壓力保護(hù)的結(jié)構(gòu)基礎(chǔ)).J.Mol.Biol.(分子生物學(xué)雜志)360，934-945(2006).20.White,S.H.MembraneProteinsofKnown3DStructure(已知3D結(jié)構(gòu)的膜蛋白).http://bianco,biomol.uci.edu/Merabrane—Proteins—xtal.html(2007).21.Morisseau,C.&Hammock,B.D.Epoxidehydrolases:Mechanisms,inhibitordesigns,andbiologicalroles(環(huán)氧化物水解酶機(jī)制、抑制劑設(shè)計(jì)、和生物學(xué)作用).Annu.Rev.Pharmacol.Toxicol.(藥理學(xué)和毒學(xué)年度綜述)45,311-+(2005).22.Corey,Ε.j.，Hopkins,P.B.,Munroe,j.Ε.,Marfat,Α.&Hash.imoto,S.TotalSynthesisof6-Trans,10-Cisand(+/~)-6-Trans,8-CisIsomersofLeukotriene-B(Q三烯-B的6-反式，10-順式和(+/-)-6-反式，8-順式異構(gòu)體的總合成)..J.Am.Chem.Soc.(美國(guó)化學(xué)協(xié)會(huì)雜志)102，7986-7987(1980).23.Morgeηsterη,R.，Svensson，R.,Bernat,B.Α.&Armstrong,R.N.Kineticanalysisoftheslowionizationofglutathionebymi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l0.0667Sl2-0.6593S13-0.5618注釋3S21-().0684S220.0140S23-().4595注釋3S31-().0809S320.6802S33-().0807注釋3注釋3TLS組2注釋3成分組的數(shù)量1注釋3成分CSSSEQITOCSSSEQI注釋3殘基范圍A6A112注釋3組(A)的來源15.2468-57.8968-10.8106注釋3T張量注釋3Tll0.1017T220.1079注釋3T330.0651T12-0.0195注釋3T13().0851T230.0219注釋3L張量注釋3Lll1.7350L221.3482注釋3L332.1370L120.4369注釋3L13-().9101L23-().5741注釋3S張量注釋3Sll-0.0534S12-0.2815S13-0.0727注釋3S210.2539S22-0.0172S230.1277注釋3S310.1175S320.0823S330.0706注釋3注釋3TLS組3注釋3成分組的數(shù)量1注釋3成分CSSSEQITOCSSSEQI注釋3殘基范圍=A113A142注釋3組(A)的來源12.8365-48.9997-38.6599注釋3T張量注釋3Tll0.0974T220.1247注釋3T330.1388T120.0022注釋3T13-0.0214T230.0643注釋3L張量注釋3Lll0.4772L221.7385注釋3L3315.5152L120.5613注釋3L131.8713L231.4990注釋3S張量注釋3Sll-().1136S120.1208S130.0559注釋3S21-().2355S220.0525S230.2362注釋3S31:-0.0451S32-0.6552S330.0611注釋3注釋3TLS組4注釋3成分組的數(shù)量1注釋3成分CSSSEQITOCSSSEQI注釋3殘基范圍A148A149注釋3組(A)的來源11.2731-46.1923-66.6381注釋3T張量注釋3Tll0.4358T220.4581注釋3T330.4564T120.0018注釋3T13-().0002T23-().0096注釋3L張量注釋3Lll22.3722L2231.1048注釋3L33224.2959Ll2-26.3796注釋3L1370.8378L23:_83.5266注釋3S張量注釋3Sll0.2737S122.4714S131.2687注釋3S21-5.2175S22:_3.9374S23:_3.9650注釋3S313.7824S321.4196S333.6637注釋3注釋3注釋3大量溶劑建模.注釋3所用方法=MASK注釋3用于MASK計(jì)算的參數(shù)注釋3VDW探針半徑1.20注釋3離子探針半徑0.80注釋3收縮半徑0.80注釋3注釋3其它精修注釋注釋3已將氫加入運(yùn)載位置注釋3CISPEP1HISA-4HISA30.00CISPEP2PROA37PROA380.00CISPEP3LEUA143ARGA1440.00CISPEP4ARGA144THRA1450.00CRYSTl169.670169.670169.67090.0090.0090.00F23規(guī)模10.0058940.0000000.0000000.00000規(guī)模20.0000000.0058940.0000000.00000規(guī)模30.0000000.0000000.0058940.00000原子1NALAA543.41756.04331.9291.0040.01N原子2CAALAA544.84656.11431.5091.0040.26C原子3CBALAA-545.609-57.239-32.2741.0039.53C原子4CALAA-545.458-54.750-31.7981.0039.87C原子50ALAA-546.544-54.674-32.3491.0040.490原子6NHISA-444.731-53.685-31.4351.0039.62N原子7CAHISA445.06152.30831.8121.0037.34C原子8CBHISA-446.450-51.924-31.2231.0036.68C原子9CGHISA-447.559-51.830-32.2331.0033.52C原子10NDlIiISA-448.441-52.864-32.4841.0031.74N原子11CElHISA-449.312-52.492-33.4061.0031.37C原子12NE2HISA449.01951.25833.7731.0030.66N原子13CD2HISA-447.931-50.816-33.0471.0028.76C原子14CHISA-445.004-52.310-33.3411.0037.04C原子150IiISA-445.628-53.147-33.9531.0036.990原子16NHISA-344.287-51.438-34.0341.0036.79N原子17CAHISA343.50150.26533.6761.0035.24C原子18CBHISA342.02050.57833.5631.0034.83C原子19CGHISA-341.652-51.796-34.3561.0036.60C原子20NDlHISA-341.549-51.785-35.7341.0035.20N原子21CElIiISA-341.284-53.008-36.1631.0037.38C原子22NE2HISA-341.227-53.817-35.1141.0035.02N原子23CD2HISA341.49653.09233.9761.0032.96C原子24CHISA-344.037-48.993-32.9851.0034.06C原子250HISA-344.487-48.964-31.8251.0034.680原子26NIiISA-243.985-47.955-33.7981.0030.69N原子27CAHISA-244.283-46.597-33.3971.0029.38C原子28CBHISA245.21846.00534.4121.0028.22C原子29CGHISA246.54246.67734.3581.0026.13C原子30NDlHISA-247.513-46.312-33.4491.0027.41N原子31CElIiISA-248.563-47.107-33.5841.0029.67C原子32NE2HISA-248.267-48.026-34.4901.0026.72N原子33CD2HISA-246.995-47.795-34.9641.0024.20C原子34CHISA243.02545.77133.1511.0029.66C原子350HISA-243.067-44.525-33.1621.0029.630原子36NHISA-141.928-46.484-32.9371.0028.29N原子37CAHISA-140.722-45.901-32.3631.0029.36C原子38CBHISA-139.833-45.269-33.4351.0029.37C原子39CGHISA139.18946.28234.3281.0029.87C原子40NDlHISA-139.843-46.855-35.3951.0027.36N原子41CElHISA-139.044-47.730-35.9761.0026.36C原子42NE2HISA-137.900-47.747-35.3181.0026.52N原子43CD2HISA-137.978-46.878-34.2611.0023.85C原子44CHISA139.97947.02931.6641.0029.58C原子450HISA140.23548.22331.8971.0027.140原子46NHISA039.084-46.641-30.7651.0030.33N原子47CAAHISA038.210-47.644-30.1560.5031.50C原子48CABHISA038.246-47.574-30.0120.5031.25C原子49CBAHISA038.709-48.065-28.7760.5031.91C原子50CBBHISA038.70847.58328.5550.5031.55C原子51CGAHISA040.193-48.215-28.6830.5034.15C原子52CCxBHISA038.350-46.341-27.7800.5031.51C原子53NDlAHISA041.012-47.196-28.2550.5036.59N原子54ND1BHISA037.046-45.965-27.5240.5032.11N原子55CElMISA042.26947.60628.2790.5037.93C原子56CE1BHISA037.031-44.870-26.7890.5029.93C原子57NE2AHISA042.288-48.862-28.6880.5036.79N原子58NE2BHISA038.284-44.520-26.5510.5035.90N原子59CD2AHISA041.003-49.268-28.9480.5036.50C原子60CD2BHISA039.12845.42227.1620.5034.28C原子61CHISA036.80347.07330.0631.0031.25C原子620HISA036.595-45.843-30.2211.0034.090原子63NHISA135.841-47.958-29.8941.0030.33N原子64CAHISA134.441-47.590-29.8161.0029.97C原子65CBHISA133.627-48.418-30.8081.0029.50C原子66CGHISA134.Oil-48.156-32.2231.OO27.56C原子67NDlHISA133.499-47.103-32.9521.0023.70N原子68CElHISA134.037-47.102-34.1551.0023.80C原子69NE2HISA134.871-48.123-34.2441.OO25.91N原子70CD2HISA134.88848.79433.0371.OO20.73C原子71CHISA133.851-47.679-28.4031.OO30.10C原子72OHISA132.636-47.579-28.2521.OO30.73O原子73NLYSA234.727-47.765-27.3951.OO29.69N原子74CALYSA234.376-47.810-25.9631.OO29.87C原子75CBLYSA235.61847.77625.0431.OO29.27C原子76CGLYSA236.41348.99925.0191.OO28.73C原子77CDLYSA237.425-48.905-23.8911.OO27.66C原子78CELYSA238.601-48.087-24.3301.OO36.28C原子79NZLYSA239.767-48.393-23.4991.OO40.53N原子80CLYSA233.570-46.603-25.5871.OO29.58C原子81OLYSA232.57546.71224.8291.OO27.29O原子82NASPA333.973-45.452-26.1261.0027.69N原子83CAASPA333.322-44.230-25.7301.OO28.51C原子84CBASPA334.195-42.983-26.0351.OO29.24C原子85CGASPA334.690-42.927-27.4981.OO34.80C原子86ODlASPA334.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0-11.7051.0039.840原子16180HOHG1619.76863.3329.6721.0034.130[1989]原子16190HOHG1711.715-77.776-5.4951.0060.380原子16200HOHG1811.013-.76.3332.5821.0056.660原子16210HOHG1912.691-69.042-15.6511.0042.530原子16220HOHG2016.776-57.005-13.2591.0046.260原子16230HOHG2111.58156.2091.0441.0042.540原子16240HOHG2215.940-62.0841.8391.0050.280原子16250HOHG236.48048.2057.9681.0057.430原子16260HOHG2439.197-43.575-30.5191.0042.040原子16270HOHG256.027-62.306-15.7881.0055.550原子16280HOHG263.80254.6176.2081.0062.400原子16290HOHG2728.505-47.616-34.3611.0065.780原子1630OWOHOHG281.80159.317-5.5751.0044.970原子1631OWOHOHG2922.373-53.791-42.7461.0056.530原子16320HOHG3020.463-67.986-5.1081.0049.860原子1633OWOHOHG311.458-52.674-5.8451.0035.480原子1634OWOHOHG32-0.601-51.527-2.0291.0056.790原子1635OWOHOHG330.72551.609-7.2061.0046.340原子1636OWOHOHG3452.333-52.336-32.5010.3362.200原子1637OWOHOHG3540.005-46.339-20.4:1.11.0051.610原子1638OWOHOHG367.348-45.031-11.0091.0067.530原子1639OWOHOHG3718.638-47.155-44.9371.0042.780原子1640OWOHOHG3842.29746.26536.4011.0059.510原子1641OWOHOHG3919.312-49.538-53.9731.0063.110原子1642OWOHOHG4012.092-61.0182.8121.0057.910原子1643OWOHOHG419.109-62.0964.8711.0064.800原子1644OffOHOHG4222.011-46.105-39.8231.0057.860原子1645OWOHOHG4346.97355.32135.4961.0069.490原子1646OWOHOHG445.887-57.239-20.6551.0060.450原子1647OWOHOHG453.287-69.706-1.4591.0073.5.70原子1648OWOHOHG4649.236-55.611-31.0521.0063.340原子16490HOHG4714.454-67.301-14.3821.0034.210原子1650OWOHOHG489.23874.1116.6841.0057.890原子1651OWOHOHG4921.087-49.042-50.3731.0056.920原子1652OWOHOHG502.13050.6544.0911.0057.030原子1653OWOHOHG516.952-49.477-5.0641.0065.410原子1654OffOHOHG525.018-51.449-3.9651.0048.620原子1655OWOHOHG539.44555.96116.9241.0035.370原子1656OWOHOHG548.917-72.072-5.1251.0050.930原子1657OWOHOHG5510.67358.1073.3251.0064.300[2028]原子1658OWOHOHG564.127-64.3214.6811.0055.090原子1659OWOHOHG5714.339-57.7130.0921.0064.040原子16600HOHG5815.953-51.995-59.07.71.0072.950原子1661OWOHOHG591.655-62.800-12.9591.0051.500原子1662OWOHOHG608.303-67.62:1-12.2061.0046.640原子1663OWOHOHG6111.164-52.3401.3701.0066.160原子1664OWOHOHG627.352-56.599-17.9791.0053.670原子1665OffOHOHG6312.595-76.1949.8470.3337.050原子1666OWOHOHG6423.621-44.970-49.2421.0067.290原子16670HOHG6516.972-53.121-66.4181.0085.950原子1668OWOHOHG663.059-73.1443.8631.0062.750原子16690HOHG677.859-48.330-32.9561.0065.260原子16700HOHG684.15658.85627.8091.0057.360原子16710HOHG694.551-59.395-29.9221.0069.100原子16720HOHG706.260-47.543-31.5861.0068.610原子16730HOHG717.840-44.03028.2461.0062.700原子16740HOHG728.079-41.411-33.2141.0072.050原子16750HOHG735.11039.11628.2291.0087.180原子16760HOHG744.809-40.681-30.6641.0089.650原子16770HOHG751.648-46.036-34.5261.0082.700原子16780HOHG7622.388-44.026-33.6641.0058.550原子16790HOHG7729.957-41.672-33.8801.0062.690原子16800HOHG785.20764.32410.1431.0037.850原子16810HOHG7912.766-53.130-50.8601.0046.090原子16820HOHG8015.500-53.938-50.0881.0060.490原子16830HOHG818.596-38.206-69.3221.0046.240原子16840HOHG8215.672-67.848-17.5781.0040.990原子16850HOHG8319.61563.96915.8811.0030.410原子16860HOHG8418.094-66.902-18.0470.3337.230原子1687OWOHOHG8511.250-67.176-16.1471.0044.940原子1688OWOHOHG8625.393-63.667-6.3841.0067.710原子1689OffOHOHG87-1.1.70-60.898-7.4731.0060.190原子1690OWOHOHG881.92360.8219.5101.0055.990原子16910HOHG895.204-75.045-0.8051.0066.560原子16920HOHG9016.440-51.952-56.6501.0053.690原子16930HOHG9117.250-43.149-41.2681.0040.840原子16940HOHG9220.290-55.7862.3191.0069.160原子16950HOHG933.67757.4116.3241.0055.590原子16960HOHG946.045-75.7751.7851.0089.590原子16970HOHG954.531-53.45035.3391.0092.620原子16980HOHG964.130-51.404-33.7341.0082.090原子16990HOHG9712.647-72.20512.6440.3378.150原子17000HOHG982.44462.6574.2851.0059.370原子17010HOHG997.480-44.064-63.5671.0062.360原子17020HOHH1　10.235　-73.92312.3621.0054.560[2073]原子17030HOHH210.853-75.04111.3530.3324.040原子17040HOHH315.894-53.2371.9911.0093.970原子17050HOHH439.197-44.633-3.7.9781.0063.140原子17060HOHH544.373-55.060-35.3761.0052.810原子17070HOHH617.661-71.389-5.5881.0043.350原子17080HOHH712.42242.24465.5411.0057.130原子17090HOHH86.038-58.327-16.6311.0068.300原子17100HOHH95.301-73.3505.4161.0076.920原子17110HOHII1023.492-43.612-31.6181.0075.360原子17:1.20HOHH1126.685-40..784-24.8621.0060.700原子17130HOHH1219.31764.6666.8381.0065.000原子17140HOHH1327.223-42.773-28.0001.0068.990原子17150HOHH141.88764.4990.6521.0057.610結(jié)束表II-具有GSH的坐標(biāo)標(biāo)題——XX-XXX-9-dasm化合物---注釋3注釋3精修.注釋3程序=REFMAC5.2.0019注釋3作者M(jìn)URSfflJD0V，VAGIN，DODSON注釋3注釋3精修目標(biāo)最大化可能性注釋3注釋3精修中使用的數(shù)據(jù).注釋3分辨率范圍高(ANGSTROMS)2.15注釋3分辨率范圍低(ANGSTROMS)49.03注釋3數(shù)據(jù)截取點(diǎn)(SIGMA(F))無注釋3范圍的完整性(％):99.66注釋3反射數(shù)量20920注釋3注釋3適合于精修中使用的數(shù)據(jù)注釋3交叉確認(rèn)方法遍及注釋3自由R值測(cè)試組選擇隨機(jī)注釋3R值(工作+測(cè)試組)0.18妨0注釋3R值(工作組)0.18301注釋3自由R值0.22024注釋3自由R值測(cè)試組尺寸(%)5.1注釋3自由R值測(cè)試組計(jì)算1129注釋3注釋3適合于最高分辨率倉[2114]注釋3使用的總倉數(shù)20注釋3倉分辨率范圍高2.153注釋3倉分辨率范圍低2.209注釋3倉中的反射(工作組)1544注釋3倉完整性(工作+測(cè)試)(%)100.00注釋3倉R值(工作組)0.245注釋3倉自由R值組計(jì)數(shù)93注釋3倉自由R值0.264注釋3注釋3精修中使用的非氫原子數(shù)量注釋3所有原子1444注釋3注釋3B值.注釋3由WILSON圖(A**2):零注釋3平均B值(總，A**2)21.523注釋3總各向異性B值注釋3Bll(A**2)零注釋3B22(A**2)零注釋3B33(A**2)零注釋3B12(A**2)零注釋3B13(A**2)零注釋3B23(A**2)零注釋3注釋3估計(jì)的總坐標(biāo)誤差.注釋3基于R值的ESU(A)0124注釋3基于自由R值的ESU(A)0.127注釋3基于最大可能性的ESU(A)0.099注釋3基于最大可能性的關(guān)于B值的ESU(A〃2):7.431注釋3注釋3相關(guān)性系數(shù)注釋3相關(guān)性系數(shù)F0-FC0.942注釋3相關(guān)性系數(shù)F0-FC自由0.921注釋3注釋3由理想數(shù)值的RMS偏差計(jì)數(shù)RMS重量注釋3鍵長(zhǎng)度精修的原子(A):1346;0.025;0.021注釋3鍵角度精修的原子(度)1811;2.485;2.033注釋3扭轉(zhuǎn)角度，1期(度)I53；6.375；5.000注釋3扭轉(zhuǎn)角度，2期(度)52；29.194；19.808注釋3扭轉(zhuǎn)角度，3期(度)I82;17.5O5；丨5.000[2153]注釋3扭轉(zhuǎn)角度,4期(度)13;19.279;15.OOO注釋3手性-中心限制(A**3)205；0.216；0.200注釋3—般平面精修的原子(A):963；0.011；0.020注釋3非鍵合接觸精修的原子(A)583；0.238；0.200注釋3非鍵合扭轉(zhuǎn)精修的原子(A)892；0.317；0.200注釋3H-鍵(X...Y)精修的原子(A)75；0.383；0.200注釋3對(duì)稱VDW精修的原子(A)102；0.227；0.200[2160]注釋3對(duì)稱H-鍵精修的原子(A)33；0.213；0.200注釋3注釋3各向同性熱因子限制.計(jì)數(shù)RMS重量注釋3主鏈鍵精修的原子(A〃2)777；1.310；1.500注釋3主鏈角度精修的原子(A**2)1199；1.935;2.000注釋3側(cè)鏈鍵精修的原子(A**2)637；3.354；3.000注釋3側(cè)鏈角度精修的原子(A〃2):610；4.793；4.500注釋3注釋3NCS限制統(tǒng)計(jì)學(xué)注釋3NCS組的數(shù)量零注釋3注釋3注釋3TLS詳細(xì)信息注釋3TLS組的數(shù)量4注釋3原子記錄僅包含剩余B因子注釋3注釋3TLS組1注釋3成分組的數(shù)量1注釋3成分CSSSEQITOCSSSEQI注釋3殘基范圍4-4A4注釋3組(A)的來源38.761030.794337.1686注釋3T張量注釋3Tll0.0263T220.0132注釋3T330.0026T12-0.0504注釋330.1.743T230.0166注釋3L張量注釋3Lll43.7540L2214.5336注釋3L338.4265L1222.5082注釋3Ll34.8297L23-2.5635注釋3S張量注釋3Sll0.4125S120.0342S130.0464注釋3S210.5494S220.3780S23-0.3859[2192]注釋3S31:0.4718S320.7522S33-().0345注釋3注釋3TLS組2注釋3成分組的數(shù)量1注釋3成分CSSSEQITOCSSSEQI注釋3殘基范圍A5A47注釋3組(A)的來源18.69174.788121.1784注釋3T張量注釋3Tll0.0778T220.0210注釋3T330.0780T12-0.0304注釋3T130.0112T230.0223注釋3L張量注釋3Lll1.6369L222.6248注釋3L333.7651L121.4943注釋3L131.4586L231.8919注釋3S張量注釋3Sll0.0517S120.0060S13-().2508注釋3S210.1396S22-().0663S23-().0501注釋3S310.5843S320.1539S330.0146注釋3注釋3TLS組3注釋3成分組的數(shù)量1注釋3成分CSSSEQITOCSSSEQI注釋3殘基范圍A48A108注釋3組(A)的來源13.655314.203529.6632注釋3T張量注釋3Tll0.0402T220.0368注釋3T330.0374Tl2-0.0427注釋3T13.0.0076T23-().0064注釋3L張量注釋3Lll1.3293L222.4856注釋3L33!.2819Ll2!.1540注釋3L130.8262L231.2899注釋3S張量注釋3Sll0.0470S120.1247S13-0.0343注釋3S21().1694S22-0.0326S230.0912注釋3S310.1021S32-().1147S33-().0143注釋3注釋3TLS組4[2231]注釋3成分組的數(shù)量1注釋3成分CSSSEQITOCSSSEQI注釋3殘基范圍A109A145注釋3組(A)的來源11.767239.243935.7931注釋3T張量注釋3Tll0.0948T220.1006注釋3T330.1232T120.0341注釋3Tl30.0316T23-0.0639注釋3L張量注釋3Lll0.7275L2219.7339注釋3L33!.6059L123.7802注釋3Ll3().6232L232.9231注釋3S張量注釋3Sll-().1412S12-().0355S130.2319注釋3S210.0911S22-0.0196S23!.1691注釋3S31:-0.2654S32-0.1500S33().1608注釋3注釋3注釋3大量溶劑建模注釋3所用方法MASK注釋3用于MASK計(jì)算的參數(shù)注釋3VDW探針半徑1.20注釋3離子探針半徑0.80注釋3收縮半徑().80注釋3注釋3其它精修注釋注釋3已將氫加入運(yùn)載位置注釋3CISPEP1HISA_4HISA_30.00CISPEP2PROA37PROA380.00CRYSTl169.940169.940169.94090.0090.0090.00F23規(guī)模10.0058840.0000000.0000000.00000規(guī)模20.0000000.0058840.0000000.00000規(guī)模30.0000000.0000000.0058840.00000原子1NHISA-445.10231.73930.7421.0043.85N原子2CAHISA-444.91232.03532.2221.0044.81C原子3CBHISA-446.04731.38333.0391.0043.72C原子4CGHISA-447.33432.14732.9891.0042.63C原子5NDlHISA-448.13932.17531.8721.0041.37N[2270]原子6CElHISA-449.19332.93732.1071.0039.60C[2271]原子7NE2HISA-449.09233.41333.3341.0039.25N原子8CD2HISA-447.94132.93533.9111.0039.51C原子9CHISA-444.95233.56832.4141.0045.14C原子100HISA-445.60534.23831.6071.0046.360原子11NHISA-344.34334.18933.4351.0045.00N原子12CAHISA343.54533.72034.5951.0044.05C原子13CBHISA-342.07533.50734.2651.0043.76C原子14CGHISA-341.62434.37333.1101.0045.31C原子15NDlHISA-341.58535.75633.1851.0044.37N原子16CElHISA-341.23436.24632.0061.0044.90C原子17NE2HISA341.04835.23731.1681.0041.90N原子18CD2HISA-341.33034.06031.8151.0042.23C原子19CHISA344.13833.07835.8751.0044.08C原子200HISA-344.66931.92835.9191.0044.840原子21NHISA-244.06933.88136.9291.0041.86N原子22CAHISA244.31333.38838.2501.0040.21C原子23CBHISA-245.26834.31438.9431.0039.35C原子24CGHISA246.60334.28138.3121.0038.72C原子25NDlHISA-247.65933.57138.8461.0040.91N原子26CElHISA-248.70633.69538.0541.0039.34C原子27NE2HISA-248.34634.41237.0031.0040.80N原子28CD2HISA-247.03634.79237.1391.0036.98C原子29CHISA243.02833.18339.0241.0039.93C原子300HISA-243.05833.19640.2601.0040.140原子31NHISA-141.91333.02438.2951.0038.27N原子32CAHISA-140.68732.42638.8601.0038.31C原子33CBHISA-139.79633.47939.4941.0037.44C原子34CGHISA139.14834.36438.4811.0037.49C原子35NDlHISA-139.82035.41437.8801.0032.64N原子36CElHISA-1.39.0:1.535.9953.7.0:1.11.0031.75C原子37NE2HISA-137.85835.34637.0081.0034.18N原子38CD2HISA-137.92634.30237.9001.0031.68C原子39CHISA139.91731.68137.7761.0037.15C原子400HISA-140.09531.91536.5681.0038.150原子41NHISA039.04130.78738.1951.0037.14N原子42CAHISA038.18530.09837.2111.0036.62C原子43CBHISA038.6.7928.6.7136.9861.0037.80C原子44CGHISA038.51627.79638.1991.0042.93C原子45NDlHISA039.57527.44239.0181.0048.02N原子46CElHISA039.12826.68540.0121.0050.57C原子47NE2HISA037.81226.55539.8821.0049.00N原子48CD2HISA037.40427.25738.7691.0045.61C原子49CHISA036.76030.04537.7461.0035.43C原子500HISA036.55430.18438.9651.0036.720原子51NHISA135.77529.83736.8821.0032.02N[2316]原子52CAHISA134.42229.83237.3581.OO30.71C原子53CBHISA133.57230.84336.6061.0030.18C原子54CGHISA133.98732.2.7136.8311.0030.69C原子55NDlHISA133.42433.06937.8011.0030.91N原子56CElHISA133.99034.25837.7901.0025.35C原子57NE2HISA134.88734.27336.8241.0030.30N原子58CD2HISA134.89233.04636.1971.0025.86C原子59CHISA133.80628.42737.2491.0030.57C原子600HISA132.58828.307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8.95.734.8641.0016.880原子1045NLEUA12714.10737.60435.5371.0014.84N原子1046CALElJA12713.37638.71536.0901.0017.03C原子1047CBLEUA12712.06838.26436.6541.0017.65C原子1048CGLEUA12710.99238.41335.6271.0026.91C原子1049CDlLEUA1279.88637.31.735.9331.0032.60C原子1050CD2LEUA12710.45439.88535.5811.0029.73C原子1051CLElJA12714.17739.43137.2211.0016.39C原子10520LEUA12714.20540.64137.2381.0016.260原子1053NALAA12814.74538.68338.1811.0016.11N原子1054CAALAA12815.56039.30139.2471.0015.78C原子1055CBALAA12816.00138.29240.2641.0015.58C原子1056CALAA12816.76140.03238.6381.0015.63C原子10570ALAA12817.15941.07039.1221.0017.530原子1058NHISA12917.29439.55637.5351.0016.41N原子1059CAHISA12918.37940.27136.8901.0016.54C原子1060CBHISA12919.11839.37135.8901.0017.13C原子1061CGHISA12920.25140.06535.2:1.71.0017.82C原子1062NDlHISA12921.49640.18535.7971.0017.71N原子1063CElHISA12922.28240.91035.0181.0017.15C原子1064NE2HISA12921.59041.26833.9501.0017.75N原子1065CD2HISA12920.32340.73134.0351.0017.93C原子1066CHISA12917.95441.61436.2231.0017.26C原子10670HISA12918.66442.60536.4071.0017.600原子1068NPHEA13016.82341.64635.4801.0015.37N原子1069CAPHEA13016.43842.78934.6711.0015.70C原子1070CBPHEA13015.86142.36533.2921.0014.48C原子1071CGPHEA13016.87541.81132.3331.0014.26C原子1072CDlPHEA13017.80342.66131.6951.0012.46C原子10.73CElPHEA13018.72642.11.730.7361.0014.66C原子1074CZPHEA13018.68340.74730.4261.0011.28C原子1075CE2PHEA13017.74139.89831.0741.009.83C原子1076CD2PHEA13016.86340.43632.0071.009.24C原子1077CPHEA13015.46843.80835.3391.0016.84C原子10.780PHEA13015.51344.97534.9881.0015.030原子1079NLEUA13114.59943.36836.2631.0018.31N原子1080CALEUA13113.48544.20236.7251.0019.33C原子1081CBLEUA13112.47143.34537.4751.0021.55C原子1082CGLEUA13111.07243.86837.7541.0024.78C原子1083CDlLEUA13110.36044.19236.4481.0024.49C原子1084CD2LEUA13110.34542.75938.5121.0027.31C原子1085CLEUA13113.94145.43437.5351.0019.75C[3350]原子10860LEUA13113.44146.53237.2721.0017.960[3351]原子1087NPROA13214.88645.26938.5001.0019.97N原子1088CAPROA13215.34546.41539.3331.0020.32C原子1089CBPROA13216.44345.79140.2481.0020.94C原子1090CGPROA13215.92144.30240.4021.0019.47C原子1091CDPROA13215.53344.01238.9441.0021.77C原子1092CPROA13215.82347.58038.5031.0019.76C原子10930PROA13215.26548.67138.6161.0020.31O原子1094NALAA13316.75647.31837.5951.0018.26N原子1095CAALAA13317.25148.36136.7681.0016.31C原子1096CBALAA13318.52147.92436.0:1.41.0014.32C原子1097CALAA13316.20648.93535.8321.0014.97C原子10980ALAA13316.21650.11935.6061.0016.490原子1099NALAA13415.30448.13635.2731.0014.39N原子1100CAALAA13414.21548.70534.4731.0013.98C原子1101CBALAA13413.45247.58833.6601.0013.38C原子1102CALAA13413.25049.57735.2801.0014.32C原子11030ALAA13412.83550.67134.7861.0014.380原子1104NLEUA13512.89449.14736.5081.0014.05N原子1105CALEUA13511.99249.95737.3171.0015.12C原子1106CBLElJA13511.51049.20338.5491.0016.20C原子1107CGLEUA13510.60147.98238.2891.0018.97C原子1108CDlLEUA13510.21847.30239.6011.0019.42C原子1109CD2LEUA1359.32948.36237.4601.0019.36C原子1110CLEUA13512.65551.30137.7331.0015.26C原子11:1.10LElJA13512.01852.38237.7341.0015.720原子1112NARGA13613.93851.21038.0771.0014.02N原子1113CAARGA13614.71652.35838.4551.0013.62C原子1114CBARGA13616.12251.95238.7961.0011.70C原子1115CGARGA13616.79953.19339.1991.0017.23C原子11:1.6CDARGA13617.99953.02139.9771.0021.91C原子1117NEARGA13619.04852.50039.1451.0027.85N原子1118CZARGA13620.32252.51239.5021.0032.97C原子1119NHlARGA13620.72153.03840.6561.0029.38N原子1120NH2MGA13621.21151.99338.6921.0038.10N原子1121CARGA13614.76653.38737.3401.0012.04C原子11220ARGA13614.52254.55137.5731.0013.000原子1123NALAA13715.04852.93436.1181.0013.52N原子1124CAALAA13715.09153.81034.9521.0013.62C原子1125CBALAA13715.63753.01333.7091.0012.85C原子1126CALAA13713.71854.41134.6611.0013.19C原子11270ALAA13713.62155.59734.3611.0013.650原子1128NALAA13812.66053.59834.7241.0013.79N原子1129CAALAA13811.28754.11134.5381.0013.40C原子1130CBALAA13810.25652.96634.7051.0012.19C原子1131CALAA13811.04855.26535.5641.0014.42C[3396]原子1132OALAA13810.66356.41935.2091.0014.090[3397]原子1133NLEUA13911.32954.97236.8331.0015.58N原子1134CALEUA13911.16355.95537.9111.0016.41C原子1135CBLEUA13911.49455.30139.2371.0017.46C原子1136CGLElJA13910.33254.70140.0251.0020.93C原子1137CDlLEUA13910.77453.39340.7151.0019.31C原子1138CD2LEUA1399.85855.84741.0001.0024.20C原子1139CLEUA13912.00.757.21537.7821.0016.65C原子11400LEUA13911.51658.30438.Oil1.OO16.20O原子1141NLElJA14013.29857.08337.4661.0017.70N原子1142CALEUA14014.11958.29637.2571.OO17.48C原子1143CBLEUA14015.57157.98036.9051.0017.06C原子1144CGLEUA14016.41357.30938.0151.OO18.21C原子1145CDlLEUA14017.75356.75437.4391.0018.45C原子1146CD2LElJA14016.6:1.058.20939.2361.0015.29C原子1147CLEUA14013.53259.19636.1651.0018.39C原子1148OLEUA14013.61960.40836.2871.0018.39O原子1149NGLYA14112.96258.57335.1231.0019.17N原子1150CAGLYA14112.26259.21134.0401.OO20.51C原子1151CGLYA14111.1:1.660.08234.5281.0021.91C原子1152OGLYA14110.97661.20234.0661.OO22.14O原子1153NARGA14210.31359.57935.4681.0023.33N原子1154CAARGA1429.24060.35036.0911.OO25.41C原子1155CBARGA1428.28459.47736.9011.OO24.99C原子1156CGARGA1427.92858.17736.2721.0030.09C原子1157CDARGA1426.47758.10935.9451.0038.07C原子1158NEARGA1426.02459.30435.2451.0044.22N原子1159CZARGA1426.45259.66934.0411.OO47.61C原子1160NHlMGA1425.97060.77733.4741.OO48.87N原子1161NH2ARGA1427.36458.92833.4111.0047.82N原子1162CARGA1429.75461.39937.0491.0026.59C原子1163OARGA1429.04362.34837.2921.0026.95O原子1164NLEUA14310.96061.24537.6021.0027.81N原子1165CAALEUA14311.45062.09738.7120.5028.31C原子1166CABLElJA14311.31962.08538.7:1.70.5028.43C原子1167CBALEUA14312.89961.76939.1670.5028.08C原子1168CBBLEUA14312.54861.54939.4620.5027.84C原子1169CGALEUA14313.45062.53740.4060.5027.82C原子1170CGBLEUA14312.21960.66440.6820.5026.49C原子1171CDIALEUA14313.15861.78141.6960.5027.48C原子1172CD1BLEUA14312.79861.28941.9380.5026.64C原子11.73CD2ALEUA14314.92962.89840.3580.5026.74C原子1174CD2BLEUA14310.71960.40440.8700.5024.63C原子1175CLEUA14311.35363.57438.3941.OO29.56C原子1176OLEUA14311.03864.37239.2741.OO29.09O[3441]原子1177NARGA14411.65263.94537.1431.0032.10N原子1178CAARGA14411.62365.39736.7011.0035.18C原子11.79CBARGA14411.71065.52335.1.701.0035.69C原子1180CGARGA14410.81964.49634.4401.0036.66C原子1181CDARGA1449.42665.05834.1071.0038.59C原子1182NEARGA1448.34864.08034.3451.0038.54N原子1183CZARGA1447.33664.24335.2081.0038.75C原子1184NHlARGA1447.22065.35135.9231.0038.78N原子1185NH2ARGA1446.41763.30035.3611.0039.05N原子1186CARGA14410.39266.1793.7.2261.0036.66C原子11870ARGA1449.36966.28136.5411.0037.300原子1188NTHRA14510.55366.78138.4141.0037.68N原子1189CATHRA1459.47367.13239.3521.0037.91C原子1190CBTHRA1459.16168.65239.2481.0038.56C原子1191OGlTHRA14510.4:1.969.33939.1321.0040.060原子1192CG2THRA1458.34969.23140.4871.0039.02C原子1193CTHRA1458.28066.12139.3141.0037.66C原子11940THRA1458.16265.17940.1061.0036.340原子1195OXTTHRA1457.39766.14238.4731.0037.900[3460]原子1196NINIB149.6:1.935.32135.3240.3343.64NI原子1197NINIB236.03236.03436.0320.3334.18NI原子119806'LMTC2-2.64114.46721.5441.0055.590原子1199C6'LMTC23.02013.50322.5201.0065.46C原子1200Cb'LMTC2-1.90312.59023.1221.0068.25C原子1201CA'LMTC2-2.52411.31123.7681.0071.6.7C原子1202C3'LMTC2-2.89711.30425.2781.0069.12C原子120303'LMTC2-4.15310.59725.5411.0065.820原子1204C2'LMTC22.81612.69925.9421.0068.48C原子120502'LMTC2-2.89212.57727.3851.0069.280原子120601*LMTC2-1.58710.25523.6381.0080.390原子1207Cl*LMTC2-2.3409.07323.4131.0088.39C原子120805*LMTC2-2.3:1.08.78022.0041.0092.280原子1209C5*LMTC23.1027.58721.9901.0094.73C原子1210C6*LMTC2-4.2267.61420.9171.0096.13C原子12:1.106*LMTC2-4.4.788.95920.4391.0099.220原子1212C4*LMTC2-2.1406.37622.2591.0092.70C原子121304*LMTC2-1.1236.20121.2361.0089.990原子1214C3*LMTC21.5186.58823.6781.0090.17C原子121503iLMTC2-1.7875.54624.6331.0087.740原子1216C2*LMTC21.9947.87924.3731.0090.31C原子121702*LMTC2-3.1007.57125.2871.0090.990原子121805'LMTC2-1.03513.20324.1031.0064.230原子1219Cl'LMTC21.64313.59825.3941.0066.28C原子122001'LMTC2-0.65213.91526.3821.0061.220原子1221ClLMTC20.32415.29326.2711.0059.74C[3486]原子1222C2LMTC20.12915.94127.5821.0058.38C原子1223C3LMTC21.65216.02927.5671.0053.65C原子1224C4LMTC22.15217.26028.2791.004.7.24C原子1225C5LMTC23.65317.04028.3791.0045.00C原子1226C6LMTC24.4731.7.30127.1201.0040.50C原子1227C7LMTC24.39118.76626.8051.0038.80C原子1228C8LMTC25.78419.27026.4611.0039.22C原子1229C9LMTC25.98420.62427.1421.0041.72C原子1230ClOLMTC27.38321.25727.0721.0040.00C原子1231CllLMTC2.7.79621.77.728.4451.0042.73C原子1232C12LMTC28.88422.86028.3451.0045.65C原子1233031GTTD17.26011.76719.7201.0018.180原子1234C3GTTD16.53410.74519.9281.0023.39C原子1235032GTTD16.7949.68119.3071.0022.210原子1236CA3GTTD15.38510.72020.93.71.0021.49C原子1237N3GTTD15.10812.04021.4611.0017.33N原子1238C2GTTD14.90612.26222.7591.0018.28C原子123902GTTD15.17011.23423.6001.0019.190原子1240CA2GTTD14.33013.56223.2681.0016.91C原子1241CB2GTTD12.90613.18523.7591.0019.79C原子1242SG2GTTD11.80812.75122.3821.0019.29S原子1243N2GTTD14.23114.57522.1631.0021.49N原子1244CDlGTTD15.15715.51521.8601.0015.20C原子1245OElGTTD16.31415.42222.5621.0019.820原子1246CGlGTTD14.98316.50020.7081.0014.16C原子1247CBlGTTD16.30816.32920.0141.0015.79C原子1248CAlGTTD16.30715.43418.7731.0023.56C原子1249NlGTTD17.58315.14218.2031.0017.29N原子1250ClGTTD15.39314.22618.4971.0022.82C原子1251OilGTTD14.48413.79519.2261.0021.170原子1252012GTTD15.58013.73617.3831.0019.190原子125302PLME126.97433.63238.8991.0066.560原子1254ClPLME127.40632.62638.2301.0066.81C原子125501PLME127.01731.44738.5191.0064.620原子1256C2PLME128.41932.83637.1001.0064.42C原子1257C3PLME128.69331.51136.3941.0060.12C原子1258C4PLME129.92131.54835.4931.0059.14C原子1259C5PLME129.75932.41734.2501.0056.91C原子1260C6PLME129.13731.61833.1241.0054.09C原子1261C7PLME128.63432.57532.0601.0051.22C原子1262C8PLME128.27631.80830.7851.0047.04C原子1263C9PLME127.52230.47430.9401.0046.76C原子1264ClOPLME127.14429.95229.5351.0044.05C原子1265CllPLME126.28828.71229.4471.0041.17C原子1266C12PLME125.11929.00828.5211.0037.05C.[3531]原子1267C13PLME124.76127.74127.7831.OO33.21C原子1268C14PLME123.36927.76227.1371.0035.38C原子1269CISPLME123.14326.41826.4491.0035.82C原子1270C16PLME122.86026.76025.0071.0036.18C原子1272ClPLME211.91438.04026.6331.0048.53C原子1274C2PLME213.17437.97025.7901.0044.77C原子1275C3PLME213.60239.36925.2871.0044.35C原子12.76C4PLME215.11439.47424.9691.0038.32C原子1277C5PLME215.51540.91824.7281.0037.07C原子1278C6PLME216.70641.17323.80.71.0035.48C原子1279C7PLME216.77442.67123.5261.0037.05C原子1280C8PLME217.97843.12922.6531.0037.63C原子1281C9PLME218.50044.55622.9281.0039.61C原子1282ClOPLME219.56145.13021.9271.0036.56C原子1290ClPLME311.54146.27643.8321.0039.81C原子1292C2PLME312.71646.96943.1611.0039.10C原子1293C3PLME312.31548.22842.4381.0035.98C原子1294C4PLME313.06849.48542.8611.0040.15C原子1295C5PLME314.26949.93442.0351.0036.54C原子1296C6PLME315.48749.92.742.9641.0037.54C原子1297C7PLME316.85950.30642.4211.0036.68C原子1298C8PLME317.84549.14242.4501.0041.16C原子1299C9PLME319.32249.52442.5051.0044.23C原子1300ClOPLME320.06048.98141.2791.0047.26C原子1308ClPLME411.8143.7.18331.8481.0045.82C原子1310C2PLME412.94337.76230.9701.0045.75C原子1311C3PLME412.89339.30030.8701.0042.36C原子1312C4PLME413.99239.81029.9281.0039.54C原子1313CbPLME413.89441.29129.5891.0037.76C原子13:1.4C6PLME415.12841.82328.8811.0036.66C原子1315C7PLME415.01943.28528.3881.0037.90C原子1316C8PLME416.31744.07728.6681.0039.17C原子1317C9PLME416.63245.42927.9931.0041.51C原子1318ClOPLME417.99146.02728.4671.0039.52C原子1326ClPLME511.32143.10132.6691.0048.99C原子1328C2PLME512.19044.15032.0161.0048.28C原子1329C3PLME511.45744.96630.9511.0050.96C原子1330C4PLME512.49045.89830.2761.0054.37C原子1331CbPLME511.91147.04229.4231.0055.82C原子1344ClPLME618.0810.22232.8741.0049.57C原子1346C2PLME619.4280.45433.1221.0049.65C原子1347C3PLME619.5381.69132.2341.0044.94C原子1348C4PLME620.9732.05931.8851.0041.84C原子1349CbPLME620.9913.57631.7641.0038.05C原子1350C6PLME622.3534.22531.6331.0041.48C[3576]原子1351C7PLME622.2315.71831.9621.OO42.77C[3577]原子1352C8PLME623.5646.37332.2611.0042.18C原子1361SS04F1-0.2120.68023.1190.5038.20S原子136201S04F1-0.012-0.44724.0800.5037.580原子136302S04F11.0380.84122.3280.5032.090原子136403S04F11.3160.32722.2060.5035.260原子136504S04F1-0.5731.81923.9850.5030.180原子13660HOHG1-0.9437.40132.5421.0037.800原子13670HOHG223.768-2.01723.4641.0050.160原子13680HOHG324.40525.63844.55.71.0030.720原子13690HOHG48.53915.18038.1791.0035.640原子13700HOHG512.649-4.1406.5711.0032.670原子13710HOHG649.19931.32729.4561.0042.680原子13720HOHG719.364-3.4543.8491.0035.880原子13730HOHG822.45422.44822.4530.3327.520原子13740HOHG924.18028.82542.8451.0031.640原子13750HOHG1015.72620.88919.7981.0028.200原子13760HOHG114.8693.90832.6951.0023.560原子13770HOHG1212.54920.95220.2701.0026.410原子13780HOHG13-0.6412.10132.5651.0030.520原子13790HOHG141.3564.20033.4331.0041.580原子13800HOHG1523.516-1.62720.7881.0027.460原子13810HOHG1612.70551.07131.7771.0039.060原子13820HOHG1719.69645.52832.8491.0046.560原子13830HOHG1820.332-4.25911.4861.0056.740原子13840HOHG196.083-4.3129.5811.0052.290原子13850HOHG2010.605-5.68510.0011.0045.470原子13860HOHG219.71416.61328.4351.0030.940原子13870HOHG2229.55023.79841.1761.0024.020原子13880HOHG2319.770-.7.17819.1711.0043.780原子13890HOHG24-0.2980.40428.3750.5017.680原子13900HOHG2519.50236.37338.6921.0028.510原子13910HOHG2618.46410.00838.9631.0047.220原子13920HOHG2717.02713.01927.8681.0023.530原子13930HOHG2816.918-11.14514.4691.0045.820原子13940HOHG293.17711.60036.1081.0030.700原子13950HOHG3016.303-2.20022.2541.0035.620原子13960HOHG313.5501.64114.2481.0038.310原子13970HOHG328.7993.17132.7661.0031.960原子13980HOHG336.5185.65413.5281.0025.160原子13990HOHG34-0.568-2.25915.3501.0038.760原子14000HOHG3511.300-1.16128.0841.0030.490原子14010HOHG3618.62145.14837.6811.0034.440原子14020HOHG378.9316.17112.3771.0037.110原子14030HOHG3819.2790.6363.0341.0040.600[3621]原子14040HOHG397.0657.0917.0760.3338.560原子14050HOHG405.1201.2789.4971.0047.240原子14060HOHG413.122-2..76734.3031.0055.080原子14070HOHG4216.4050.43135.0121.0060.690原子14080HOHG439.34156.82932.9531.0047.190原子14090HOHG4413.7492.87535.7821.0046.750原子14100HOHG4521.044-4.63224.3531.0048.950原子14110HOHG4617.96017.97218.0230.3321.660原子14120HOHG4723.465-4.35119.2231.0046.630原子14:1.30HOHG4822.105-6.22819.9:1.01.0040.950原子14140HOHG4913.57113.57213.5720.3339.270原子14150HOHG507.07952.77547.7151.0043.720原子14160HOHG519.00949.99633.0511.0051.940原子14170HOHG5210.26241.23127.8951.0049.000原子14:1.80HOHG5313.72013.66912.8:1.30.3318.060原子14190HOHG5416.5279.71914.2141.0041.630原子14200HOHG5519.917-2.46129.0081.0041.310原子14210HOHG5626.0024.11327.9271.0043.020原子14220HOHG5742.53037.63135.7391.0044.030原子14230HOHG580.55823.09729.7641.0038.420原子14240HOHG59-0.08420.76628.6791.0042.630原子14250HOHG607.23131.65732.1461.0049.340原子14260HOHG616.10028.75733.7511.0048.450原子14270HOHG6222.70433.26241.1191.0043.750原子14280HOHG6323.54236.67845.2831.0056.290原子14290HOHG6413.01315.64816.0661.0033.590原子14300HOHG6511.92311.53937.8961.0032.510原子14310HOHG6623.799-0.42230.8081.0042.750原子14320HOHG6719.8488.64134.9461.0045.990原子14330HOHG686.2848.08836.2461.0032.450原子14340HOHG6916.32062.60837.9371.0054.040原子14350HOHG7017.34760.40834.2611.0051.340原子14360HOHG7123.68661.09738.4821.0047.830原子14370HOHG721.2615.92931.4801.0026.590原子14380HOHG7315.53914.90626.7751.0015.990原子14390HOHG7414.98414.22517.5211.0025.280原子14400HOHG7510.75210.75310.7520.3344.690原子14410HOHG767.9510.9263.3741.0052.970原子14420HOHG775.3532.1296.3011.0046.990原子14430HOHG783.7613.6462.8220.3323.220原子14440HOHG795.7362.1982.3481.0056.670原子14450HOHG8016.99615.73117.6211.0032.020原子14460HOHG819.5099.33612.4461.0027.310原子14470HOHG827.28563.62841.2551.0050.120原子14480HOHG8311.66871.67437.3941.0058.950[3666]原子1449OHOHG8452.50227.81739.2091.0054.210原子14500HOHG8522.73036.64742.7841.0052.190原子14510HOHG8617.00545.98632.9231.0030.940原子14520HOHG879.49947.98033.7721.0040.660原子14530HOHG885.05256.4:1.538.4301.0055.240原子14540HOHG8922.8071.14425.4601.0042.510原子14550HOHG9025.2341.91925.8831.0052.430原子14560HOHG9121.54910.61219.5101.0036.050原子14570HOHG928.615-0.8226.9481.0049.680原子14580HOHG9311.375-2.2652.6081.0028.010原子14590HOHG9410.5632.1348.0361.0027.900原子14600HOHG953.858-0.50512.0821.0037.250原子14610HOHG9617.84562.18436.5681.0060.670原子14620HOHG9719.88363.50038.5501.0051.500原子14630HOHG98-3.99212.18233.3451.0047.540原子14640HOHG992.62514.17234.2891.0057.660原子14650HOHH1-1.41016.22232.3521.0051.790原子14660HOHH2-2.0354.9204.2131.0056.430原子14670HOHH31.7622.1813.1380.339.550原子14680HOHH44.071-1.1422.3761.0070.240原子14690HOHH52.3680.0851.2871.0056.000原子14700HOHH63.459-6.49115.1911.0043.500原子14710HOHH72.6113.26423.6031.0027.950原子14720HOHH82.1700.59119.7461.0052.430原子14730HOHH92.1700.59119.7461.0052.430原子14740HOHH1022.20728.31748.7431.0045.790原子14750HOHH1114.592-1.03624.6061.0038.070原子14760HOHH124.4624.94321.4081.0041.790原子14770HOHH1315.67556.88533.1191.0046.320原子14780HOHH1418.46951.76336.1531.0038.330原子14790HOHH1512.448-6.5218.3821.0045.620原子14800HOHH1612.13065.81442.9.711.0038.190原子14810HOHH1725.95829.22939.2471.0044.500原子14820HOHH1826.611-2.74516.9701.0051.780原子14830HOHH199.680-2.08121.8971.0038.190原子14840HOHH205.879-4.83525.8221.0040.980原子14850HOHH2122.45842.6.7931.7671.0040.480原子14860HOHH2212.2419.4278.7551.0054.060原子14870HOHH235.205-5.01317.3611.0035.530原子14880HOHH2416.4730.8624.4891.0041.630原子14890HOHH257.86061.36830.8031.0053.110原子14900HOHH2613.0.7763.13035.9.751.0048.460原子14910HOHH2742.30536.49037.7691.0045.840結(jié)束權(quán)利要求用于選擇或設(shè)計(jì)預(yù)期調(diào)節(jié)白三烯C4合酶(LTC4S)活性的化合物的方法，所述方法包括使用分子建模方式選擇或設(shè)計(jì)預(yù)期與LTC4S的催化位點(diǎn)或底物結(jié)合區(qū)相互作用的化合物的步驟，其中將LTC4S的催化位點(diǎn)或底物結(jié)合區(qū)的至少一部分的三維結(jié)構(gòu)與化合物的三維結(jié)構(gòu)進(jìn)行比較，并選擇預(yù)期與所述催化位點(diǎn)或底物結(jié)合區(qū)相互作用的化合物。2.權(quán)利要求1的方法,其中LTC4S的活性位點(diǎn)或底物結(jié)合區(qū)的至少一部分的三維結(jié)構(gòu)是對(duì)包含N端六組氨酸標(biāo)記物的LTC4S多肽所確定的三維結(jié)構(gòu)(或其部分)。3.權(quán)利要求1或權(quán)利要求2的方法，其中LTC4S的活性位點(diǎn)或底物結(jié)合區(qū)的至少一部分的三維結(jié)構(gòu)是對(duì)人LTC4S多肽所確定的三維結(jié)構(gòu)(或其部分)。4.前述權(quán)利要求中任一項(xiàng)的方法,其中LTC4S的活性位點(diǎn)或底物結(jié)合區(qū)的至少一部分的三維結(jié)構(gòu)是可通過晶體的X射線分析獲得的三維結(jié)構(gòu)(或其部分),所述晶體可利用包含去污劑的母液溶液獲得。5.權(quán)利要求4的方法，其中所述去污劑是十二烷基麥芽糖苷(DDM)。6.前述權(quán)利要求中任一項(xiàng)的方法,其中所述母液溶液包含谷胱甘肽(GSH)。7.權(quán)利要求1-5中任--項(xiàng)的方法,其中LTC4S的活性位點(diǎn)或底物結(jié)合區(qū)的至少一部分的三維結(jié)構(gòu)是通過表I中所示的結(jié)構(gòu)坐標(biāo)表示的結(jié)構(gòu)(或其部分)，或關(guān)于所述結(jié)構(gòu)坐標(biāo)士來自所述蛋白質(zhì)主鏈原子的小于2.0A,1.5A,1.0A或0.5A的均方根偏差建模的結(jié)構(gòu)。8.權(quán)利要求1-4中任一項(xiàng)或6的方法，其中LTC4S的活性位點(diǎn)或底物結(jié)合區(qū)的至少一部分的三維結(jié)構(gòu)是通過表II中所示的結(jié)構(gòu)坐標(biāo)表示的結(jié)構(gòu)(或其部分)，或關(guān)于所述結(jié)構(gòu)坐標(biāo)士來自所述蛋白質(zhì)主鏈原子的小于2.0A,1.5A,1.0A或0.5A的均方根偏差建模的結(jié)構(gòu)。9.前述權(quán)利要求中任一項(xiàng)的方法,其中所選擇的化合物預(yù)期封閉或結(jié)合稱為“GSH底物結(jié)合腔”(由包括全長(zhǎng)人LTC4S的殘基Arg51,Arg30,Argl04,Gln53,Asn55,Glu58,Tyr59,Tyr93,Tyr97,Ile27,Pro37,LeulOS的殘基，或等價(jià)殘基形成)；“親脂性底物結(jié)合裂隙”(由包括Ala20,Leu24,Ile27，Tyr59,Trpll6,Alall2,LeullS,Leu108,Tyrl09,Leu62,Val119,Thr66,Vall6和Leul7的殘基,或等價(jià)殘基形成)；或“催化位點(diǎn)”(由包括ArgliM或Arg31的殘基，或等價(jià)殘基形成)的結(jié)構(gòu)區(qū)域的至少一部分。10.前述權(quán)利要求中任一項(xiàng)的方法，還包括合成、純化和/或配制所選擇的化合物的步驟.11.前述權(quán)利要求中任一項(xiàng)的方法，包括評(píng)估所述化合物是否調(diào)節(jié)LTC4S活性,和選擇調(diào)節(jié)所述活性的化合物的步驟。12.前述權(quán)利要求中任一項(xiàng)的方法，包括評(píng)估所述化合物是否調(diào)節(jié)全細(xì)胞、組織或器官中的LTC4的信號(hào)傳導(dǎo)，和選擇調(diào)節(jié)所述活性的化合物的步驟。13.權(quán)利要求12的方法，還包括評(píng)估所述化合物是否調(diào)節(jié)全細(xì)胞、組織或器官中的LTC4S活性,和選擇調(diào)節(jié)所述活性的化合物的步驟。14.權(quán)利要求10-13中任一項(xiàng)的方法，還包括合成、純化和/或配制所選擇的化合物的步驟。15.制備調(diào)節(jié)LTC4S的活性的化合物的方法,所述方法包括1)執(zhí)行按照權(quán)利要求1-14中任--項(xiàng)的方法,和2)合成、純化和/或配制所選擇的化合物。16.突變的LTC4S多肽，其中突變與全長(zhǎng)人LTC4S的Arg51,Arg30,Argl04,Gln53,Asn55,Glu58,Tyr59,Tyr93,Tyr97,Ile27,Pro37,Leu108,Ala20,Leu24,Ile27,Tyr59,Trpl16,Alall2，LeullS,Leu108,Tyrl09,Leu62,Valll9,Thr66,Val16和Leu17或Arg31等價(jià)的一種或多種殘基。17.編碼按照權(quán)利要求16的突變LTC4S的多核苷酸。18.按照權(quán)利要求17的多核苷酸，其適合于表達(dá)按照權(quán)利要求16的突變LTC4S。19.宿主細(xì)胞，其包括按照權(quán)利要求17或18的多核苷酸。20.制備按照權(quán)利要求16的突變LTC4S的方法,所述方法包括培養(yǎng)按照權(quán)利要求19的表達(dá)所述突變的LTC4S的宿主細(xì)胞,和分離所述突變的LTC4S。21.可通過權(quán)利要求20的方法獲得的突變的LTC4S。22.鑒定或表征調(diào)節(jié)LTC4S活性的化合物的方法，包括確定化合物對(duì)按照權(quán)利要求16或21中任一項(xiàng)的突變LTC4S的活性的作用，或化合物結(jié)合按照權(quán)利要求16或21中任一項(xiàng)的突變LTC4S的能力的步驟。23.權(quán)利要求22的方法，還包括確定化合物對(duì)不如權(quán)利要求16或21定義的那樣突變的LTC4S的活性的作用，或化合物結(jié)合不如權(quán)利要求16或21定義的那樣突變的LTC4S的能力的步驟。24.多部件試劑盒,包括(1)按照權(quán)利要求16或21的突變的LTC4S(2)不如權(quán)利要求16或21定義的那樣突變的相應(yīng)LTC4S。25.如權(quán)利要求中任一項(xiàng)定義的多肽的三維晶形。26.權(quán)利要求25的晶形,其屬于空間群F23和/或具有包含48條LTC4S鏈的晶胞和/或包括由金屬離子配位的多個(gè)鄰近組氨酸標(biāo)記物(例如對(duì)于每個(gè)LTC4S三聚體是3個(gè)或?qū)τ诿總€(gè)晶胞是12個(gè))。27.權(quán)利要求25或26的三維晶形，其中所述晶形還包括共結(jié)晶分子。28.權(quán)利要求27的三維晶形,其中共結(jié)晶分子是GSH或去污劑諸如DDM。29.權(quán)利要求27或28的三維晶形,其中共結(jié)晶分子調(diào)節(jié)LTC4S活性。30.用于制備或試圖制備按照權(quán)利要求25-29中任一項(xiàng)的晶形的方法，包括1)提供如權(quán)利要求1-3中任一項(xiàng)中所定義的多肽；2)提供利用按照權(quán)利要求1-14中任一項(xiàng)的方法選擇的化合物；和3)對(duì)包含如權(quán)利要求1-3中任一項(xiàng)定義的多肽和所選擇的化合物的組合物進(jìn)行結(jié)晶試驗(yàn)。31.權(quán)利要求1-3中任一項(xiàng)定義的多肽的用途，其用于產(chǎn)生LTC4S的活性位點(diǎn)或底物結(jié)合區(qū)(或其一部分)的晶體或結(jié)構(gòu)；或與測(cè)試化合物結(jié)合的LTC4S的活性位點(diǎn)或底物結(jié)合區(qū)(或其一部分)的晶體或結(jié)構(gòu)。32.權(quán)利要求1-14中任一項(xiàng)的方法,還包括對(duì)包含如權(quán)利要求1-3中任一項(xiàng)定義的多肽和所選擇的化合物的組合物進(jìn)行結(jié)晶試驗(yàn)的步驟。33.預(yù)測(cè)靶LTC4S蛋白或其他MAPEG家族成員蛋白或其(靶蛋白)同源或異源多聚體的三維結(jié)構(gòu)的方法，所述方法包括下述步驟比對(duì)所述靶蛋白的氨基酸序列的表示和任選地以不大于2.0A,1.5A,1.0A或0.5A的均方根偏差變化的表I或H的LTC4S的氨基酸序列，或其選定的坐標(biāo)，從而使氨基酸序列的同源區(qū)匹配；關(guān)于如表I或II所定義的LTC4S結(jié)構(gòu)的相應(yīng)區(qū)域或其選定的坐標(biāo)對(duì)所述靶蛋白的匹配同源區(qū)的結(jié)構(gòu)建模，所述如表I或II所定義的LTC4S結(jié)構(gòu)任選地以不大于2.0A,1.5人，1.0A或0.5A的均方根偏差變化；和確定所述靶蛋白的構(gòu)象,其基本保持所述匹配的同源區(qū)的結(jié)構(gòu)。34.獲得靶LTC4S蛋白或其他MAPEG家族成員蛋白或其(靶蛋白)同源或異源多聚體結(jié)構(gòu)的方法，所述方法包括以F步驟提供所述靶蛋白的晶體；獲得所述晶體的X射線衍射圖；通過關(guān)于表I或II的LTC4S結(jié)構(gòu)士來自蛋白質(zhì)主鏈原子的小于2.0A,1.5A,1.0A或0.5A的均方根偏差或其選定的坐標(biāo)對(duì)所述靶蛋白的結(jié)構(gòu)建模，計(jì)算所述靶蛋白三維原子坐標(biāo)結(jié)構(gòu)。35.用于選擇或設(shè)計(jì)預(yù)期調(diào)節(jié)MAPEG家族成員蛋白或其同源或異源多聚體的活性的化合物的方法，所述方法包括使用分子建模方式選擇或設(shè)計(jì)預(yù)期與MAPEG家族成員蛋白或其同源或異源多聚體的催化位點(diǎn)或底物結(jié)合區(qū)相互作用的化合物的步驟，其中MPEG家族成員蛋白或其同源或異源多聚體的催化位點(diǎn)或底物結(jié)合區(qū)的至少一部分的三維結(jié)構(gòu)與化合物的三維結(jié)構(gòu)比較,和選擇預(yù)期與所述催化位點(diǎn)或底物結(jié)合區(qū)相互作用的化合物，其中MAPEG蛋白或其同源或異源多聚體的催化位點(diǎn)或底物結(jié)合區(qū)的至少一部分的三維結(jié)構(gòu)是通過按照權(quán)利要求33，34或44的方法預(yù)測(cè)或獲得的三維結(jié)構(gòu)(或其一部分)。36.權(quán)利要求1-14中任一項(xiàng)或權(quán)利要求35的方法,其中待擬合的分子結(jié)構(gòu)采用藥效團(tuán)模型的形式。37.基于計(jì)算機(jī)的合理藥物設(shè)計(jì)方法，包括(a)提供如表I或II定義的LTC4S結(jié)構(gòu)的坐標(biāo),其任選地以小于2.0A,1.5A,1.0A或0.5A的蛋白質(zhì)主鏈原子均方根偏差變化，或其選定的坐標(biāo)；(b)提供許多分子片段的結(jié)構(gòu)；(c)使各種分子片段的結(jié)構(gòu)擬合選定的坐標(biāo)；和(d)將所述分子片段裝配為單分子以形成候選調(diào)節(jié)分子。38.權(quán)利要求37的方法，還包括下述步驟(a)獲得或合成分子片段或調(diào)節(jié)分子；和(b)使所述分子片段或調(diào)節(jié)分子與LTC4S相接觸以確定所述分子片段或調(diào)節(jié)分子與LTC4S相互作用的能力。39.獲得LTC4S三維結(jié)構(gòu)表示的方法，所述方法包括提供表I或II的數(shù)據(jù)，其任選以小于2.0A,1.5A,1.0A或0.5A的蛋白質(zhì)主鏈原子均方根偏差變化，或其選定的坐標(biāo)，和構(gòu)建表示所述坐標(biāo)的三維結(jié)構(gòu)。40.權(quán)利要求39的方法，其中所述結(jié)構(gòu)表示為，(a)網(wǎng)架模型；(b)網(wǎng)狀模型；(C)球-棒狀模型；⑷空間填充模型；(e)棒狀模型；(f)帶狀模型；(g)蛇形模型；(h)箭-圓柱模型；(i)電子密度圖；(j)分子表面模型。41.一種計(jì)算機(jī)系統(tǒng),其意欲產(chǎn)生化合物的結(jié)構(gòu)和/或進(jìn)行對(duì)其進(jìn)行最優(yōu)化,所述化合物與LTC4S或其他MAPEG家族成員蛋白或其同源或異源多聚體，LTC4S或其他MAPEG家族成員蛋白或其同源或異源多聚體與化合物的復(fù)合物相互作用，所述包含計(jì)算機(jī)可讀數(shù)據(jù)的系統(tǒng)包括以下各項(xiàng)中的一種或多種(a)表I或II的LTC4S坐標(biāo)數(shù)據(jù),其任選地以小于22.0A,1.5A,1.0A或0.5A的蛋白質(zhì)主鏈原子均方根偏差變化,或其選定的坐標(biāo)；所述數(shù)據(jù)定義LTC4S或其所述選定的坐標(biāo)的三維結(jié)構(gòu)；(b)靶MAPEG家族成員蛋白或其同源或異源多聚體的原子坐標(biāo)數(shù)據(jù),其通過基于表I或II的坐標(biāo)數(shù)據(jù),其任選地以小于2.0A,1.5A,1.0A或0.5A的蛋白質(zhì)主鏈原子均方根偏差變化,或其選定的坐標(biāo)對(duì)靶標(biāo)同源建模產(chǎn)生；(c)靶MAPEG家族成員蛋白或其同源或異源多聚體的原子坐標(biāo)數(shù)據(jù),其通過參考表I或II的坐標(biāo)數(shù)據(jù),其任選地以小于2.0A,1.5A’1.0A或0.5A的蛋白質(zhì)主鏈原子均方根偏差變化,或其選定的坐標(biāo)解釋X射線晶體數(shù)據(jù)或NMR數(shù)據(jù)產(chǎn)生；(d)可來源于(b)或(c)的原子坐標(biāo)數(shù)據(jù)的結(jié)構(gòu)因子數(shù)據(jù)；和(e)表I或II的原子坐標(biāo)數(shù)據(jù),其任選地以小于2.0A,1.5A,1.0A或0.5A的蛋白質(zhì)主鏈原子均方根偏差變化，或其選定的坐標(biāo)。42.按照權(quán)利要求41的計(jì)算機(jī)系統(tǒng)，其中所述原子坐標(biāo)數(shù)據(jù)關(guān)于通過權(quán)利要求9中列舉的殘基提供的原子中的至少一種。43.用于選擇或設(shè)計(jì)預(yù)期調(diào)節(jié)白三烯C4合酶(LTC4S)活性的化合物的方法,所述方法包括使用分子建模方式選擇或設(shè)計(jì)預(yù)期與LTC4S的亞單位相互作用區(qū)相互作用的化合物的步驟，其中LTC4S的亞單位相互作用區(qū)的至少一部分的三維結(jié)構(gòu)與化合物的三維結(jié)構(gòu)相比較,和選擇預(yù)期與所述底物相互作用區(qū)相互作用的化合物。44.用于獲得靶LTC4S蛋白或其他MAPEG家族成員蛋白或其(靶蛋白)同源或異源多聚體的結(jié)構(gòu)的方法，所述方法包括以下步驟提供所述靶蛋白的晶體；獲得所述晶體的電子衍射圖；通過表I或II的LTC4S結(jié)構(gòu)士來自蛋白質(zhì)主鏈原子的小于2.0A,優(yōu)選小于1.5A,1.0,或0.5A的均方根偏差或其選定的坐標(biāo)上的所述靶蛋白的結(jié)構(gòu)建模，計(jì)算所述靶蛋白三維原子坐標(biāo)結(jié)構(gòu)。全文摘要用于選擇或設(shè)計(jì)預(yù)期調(diào)節(jié)白三烯C4合酶(LTC4S)的活性的化合物的方法，所述方法包括使用分子建模方式選擇或設(shè)計(jì)預(yù)期與LTC4S的催化位點(diǎn)或底物結(jié)合區(qū)相互作用的化合物的步驟，其中LTC4S的催化位點(diǎn)或底物結(jié)合區(qū)的至少一部分的三維結(jié)構(gòu)與化合物的三維結(jié)構(gòu)相比較，和選擇預(yù)期與所述催化位點(diǎn)或底物結(jié)合區(qū)相互作用的化合物。選擇的化合物可以預(yù)期結(jié)合稱為“GSH底物結(jié)合腔”(由包括全長(zhǎng)人LTC4S的殘基Arg51，Arg30，Arg104，Gln53，Asn55，Glu58，Tyr59，Tyr93，Tyr97，Ile27，Pro37，Leu108的殘基，或等價(jià)殘基形成)；“親脂性底物結(jié)合裂隙”(由包括Ala20，Leu24，Ile27，Tyr59，Trp116，Ala112，Leu115，Leu108，Tyr109，Leu62，Val119，Thr66，Val16和Leu17的殘基，或等價(jià)殘基形成)；或“催化位點(diǎn)”(由包括Arg104或Arg31的殘基，或等價(jià)殘基形成)的結(jié)構(gòu)區(qū)域的至少一部分。文檔編號(hào)G06F19/16GK101816001SQ200880023356公開日2010年8月25日申請(qǐng)日期2008年5月7日優(yōu)先權(quán)日2007年5月18日發(fā)明者丹尼爾·馬丁內(nèi)斯·莫利納,安德斯·韋特霍爾姆,安德烈亞斯·科爾,帕爾·努德隆德,杰西帕·Z·黑格斯特羅姆,薩德·埃沙格伊申請(qǐng)人:比奧里波克斯公司