Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters.
Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters.
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DOI：
10.1111/j.1742-4658.2010.07771.x
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发表时间：
2010-09
期刊：
影响因子：
--
通讯作者：
Weber IT
中科院分区：
文献类型：
--
作者：
Shen CH;Wang YF;Kovalevsky AY;Harrison RW;Weber IT
用野生型酶和耐药常见的V32I、I50V、I54V、I54M、I84V和L90M单取代突变株，分析了临床使用的HIV蛋白酶(PR)抑制剂氨丙那韦(APV)的结构和动力学效应。APV络合物的晶体结构在1.02到1.85ó的分辨率下揭示了由于突变而引起的结构变化。PRV32I、PRI54M和PRL90M中较大的侧链被取代后，分别与翻盖残基79和80以及Asp25形成了新的疏水接触。突变为较小的侧链消除了PRI50V和PRI54V结构中的疏水相互作用。PRI84V-APV复合体失去了与APV的疏水接触，PRV32I-APV复合体与APV疏水簇内的疏水接触增加，PRI50V复合体与APV的极性和疏水作用较弱。PRI84V-APV、PRV32I-APV和PRI50V-APV的结构变化与APV的抑制率分别为野生型PR的6倍、10倍和30倍有关。并与相应的沙奎那韦(SQV)络合物进行了比较。PR二聚体具有明显的襟翼和80‘S环的重排，适应于不同的抑制剂P1’基团，同时保持疏水簇内的接触。这些循环中的微小变化和微弱的内部相互作用产生了这两种药物不同的耐药突变模式。
The structural and kinetic effects of amprenavir (APV), a clinical HIV protease (PR) inhibitor, were analyzed with wild type enzyme and mutants with single substitutions of V32I, I50V, I54V, I54M, I84V and L90M that are common in drug resistance. Crystal structures of the APV complexes at resolutions of 1.02 to 1.85 Å reveal the structural changes due to the mutations. Substitution of the larger side chains in PRV32I, PRI54M and PRL90M resulted in formation of new hydrophobic contacts with flap residues, residues 79 and 80, and Asp25, respectively. Mutation to smaller side chains eliminated hydrophobic interactions in the PRI50V and PRI54V structures. The PRI84V-APV complex had lost hydrophobic contacts with APV, the PRV32I-APV complex showed increased hydrophobic contacts within the hydrophobic cluster, and the PRI50V complex had weaker polar and hydrophobic interactions with APV. The observed structural changes in PRI84V-APV, PRV32I-APV and PRI50V-APV were related to their reduced inhibition by APV of 6-, 10- and 30-fold, respectively, relative to wild type PR. The APV complexes were compared with the corresponding saquinavir (SQV) complexes. The PR dimers had distinct rearrangements of the flaps and 80’s loops that adapt to the different P1′ groups of the inhibitors while maintaining contacts within the hydrophobic cluster. These small changes in the loops and weak internal interactions produce the different patterns of resistant mutations for the two drugs.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
8
作者：
Hong, L;Zhang, XJC;Tang, J
通讯作者：
Tang, J
DOI：
10.1073/pnas.86.15.5781
发表时间：
1989-08-01
影响因子：
11.1
作者：
GOTTLINGER, HG;SODROSKI, JG;HASELTINE, WA
通讯作者：
HASELTINE, WA
影响因子：
5.6
作者：
Heaslet, H;Kutilek, V;Stout, CD
通讯作者：
Stout, CD
影响因子：
64.8
作者：
KELLIS, JT;NYBERG, K;FERSHT, AR
通讯作者：
FERSHT, AR