Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor

被引:187
作者
Esnouf, RM
Ren, JS
Hopkins, AL
Ross, CK
Jones, EY
Stammers, DK
Stuart, DI
机构
[1] UNIV OXFORD, MOL BIOPHYS LAB, OXFORD OX1 3QU, ENGLAND
[2] OXFORD CTR MOL SCI, OXFORD OX1 3QU, ENGLAND
[3] CATHOLIC UNIV LEUVEN, REGA INST MED RES, B-3000 LOUVAIN, BELGIUM
[4] GLAXO WELLCOME RES & DEV LTD, BECKENHAM BR3 3BS, KENT, ENGLAND
关键词
delavirdine; AIDS; drug design; x-ray crystallography;
D O I
10.1073/pnas.94.8.3984
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The viral reverse transcriptase (RT) provides an attractive target in the search for anti-HIV therapies. The nonnucleoside inhibitors (NNIs) are a diverse set of compounds (usually HIV-1 specific) that function by distorting the polymerase active site upon binding in a nearby pocket. Despite being potent and of generally low toxicity, their clinical use has been limited by rapid selection for resistant viral populations. The 2.65-Angstrom resolution structure of the complex between HIV-1 RT and the bis(heteroaryl) piperazine (BHAP) NNI, 1-(5-methanesulfonamido-1H-indol-2-ylcarbonyl)-4- [3-(1-methyl-ethylamino)pyridinyl] piperazine (U-90152), reveals the inhibitor conformation and bound water molecules. The bulky U-90152 molecule occupies the same pocket as other NNIs, but the complex is stabilized quite differently, in particular by hydrogen bonding to the main chain of Lys-103 and extensive hydrophobic contacts with Pro-236. These interactions rationalize observed resistance mutations, notably Pro-236-Leu, which occurs characteristically for BHAPs. When bound, part of U-90152 protrudes into the solvent creating a channel between Pro-236 and the polypeptide segments 225-226 and 105-106, giving the first clear evidence of the entry mode for NNIs. The structure allows prediction of binding modes for related inhibitors [(altrylamino)piperidine-BHAPs] and suggests changes to U-90152, such as the addition of a 6 amino group to the pyridine ring, which may make binding more resilient to mutations in the RT. The observation of novel hydrogen bonding to the protein main chain may provide lessons for the improvement of quite different inhibitors.
引用
收藏
页码:3984 / 3989
页数:6
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