HIV-1蛋白酶突变体的超高分辨率晶体结构揭示了临床抑制剂TMC114的两个结合位点。
Ultra-high resolution crystal structure of HIV-1 protease mutant reveals two binding sites for clinical inhibitor TMC114.
作者信息
Kovalevsky Andrey Y, Liu Fengling, Leshchenko Sofiya, Ghosh Arun K, Louis John M, Harrison Robert W, Weber Irene T
机构信息
Department of Biology, Molecular Basis of Disease, GA State University, Atlanta, GA 30303, USA.
出版信息
J Mol Biol. 2006 Oct 13;363(1):161-73. doi: 10.1016/j.jmb.2006.08.007. Epub 2006 Aug 4.
Abstract
TMC114 (darunavir) is a promising clinical inhibitor of HIV-1 protease (PR) for treatment of drug resistant HIV/AIDS. We report the ultra-high 0.84 A resolution crystal structure of the TMC114 complex with PR containing the drug-resistant mutation V32I (PR(V32I)), and the 1.22 A resolution structure of a complex with PR(M46L). 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 inhibitors.
摘要
TMC114（地瑞那韦）是一种很有前景的用于治疗耐药性HIV/AIDS的HIV-1蛋白酶（PR）临床抑制剂。我们报道了TMC114与含有耐药性突变V32I的PR（PR(V32I)）形成的复合物的超高分辨率（0.84 Å）晶体结构，以及与PR(M46L)形成的复合物的1.22 Å分辨率结构。这些结构显示TMC114结合在两个不同的位点，一个在活性位点腔中，另一个在PR二聚体中一个柔性侧翼的表面上。值得注意的是，TMC114通过磺酰胺氮的反转以两种非对映异构体同时结合在这两个位点。此外，侧翼位点的形状适合容纳具有S-对映体氮的非对映异构体，而不是具有R-对映体氮的非对映异构体。第二个结合位点和两种非对映异构体的存在揭示了TMC114对耐药性HIV高效作用的机制以及新抑制剂的潜在设计思路。
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