Ultra-high resolution crystal structure of HIV-1 protease mutant reveals two binding sites for clinical inhibitor TMC114
Ultra-high resolution crystal structure of HIV-1 protease mutant reveals two binding sites for clinical inhibitor TMC114
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DOI：
10.1016/j.jmb.2006.08.007
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发表时间：
2006-10-13
影响因子：
5.6
通讯作者：
Weber, Irene T.
中科院分区：
文献类型：
--
作者：
Kovalevsky, Andrey Y.;Liu, Fengling;Weber, Irene T.
TMC114(达鲁那韦)是一种很有前途的HIV-1蛋白酶(PR)临床抑制剂，用于治疗耐药的HLV/AIDS。我们报道了含有耐药突变V321(PRV321)的TMC114配合物的超高0.84埃分辨晶体结构，以及含有PRM46L的配合物的1.22埃分辨结构。这些结构显示TMC114结合在两个不同的位置，一个在活性中心空腔中，另一个在PR二聚体中一个柔性折叠的表面上。值得注意的是，TMC114同时与这两个位置上的两个非对映异构体结合，这两个非对映异构体通过磺胺氮的倒置相关。此外，襟翼位置的形状是为了容纳带有S对映体氮的非对映异构体，而不是带有R-对映体氮的非对映异构体。第二结合位点和两个非对映异构体的存在提示了TMC114治疗耐药HIV的高效机制和新的潜在设计。爱思唯尔有限公司出版。
TMC114 (darunavir) is a promising clinical inhibitor of HIV-1 protease (PR) for treatment of drug resistant HlV/AIDS. We report the ultra-high 0.84 angstrom resolution crystal structure of the TMC114 complex.with PR containing the drug-resistant mutation V321 (PRV321), and the 1.22 angstrom resolution structure of a complex with PRM46L. These structures show TMC114 bound at two distinct sites, one in the active-site cavity and the second on the surface of one of the flexible flaps in the PR dimer. Remarkably, TMC114 binds at these two sites simultaneously in two diastereomers related by inversion of the sulfonamide nitrogen. Moreover, the flap site is shaped to accommodate the diastereomer with the S-enantiomeric nitrogen rather than the one with the R-enantiomeric nitrogen. The existence of the second binding site and two diastereomers suggest a mechanism for the high effectiveness of TMC114 on drug-resistant HIV and the potential design of new. Published by Elsevier Ltd.