Crystal structure of chemically synthesized HIV-1 protease and a ketomethylene isostere inhibitor based on the p2/NC cleavage site (Reprinted from Bioorg. Med. Chem. Lett., vol 18, pg 4554-4557, 2008)

被引：2

作者：

Torbeev, Vladimir Yu. ^{[1
,2
]}

Mandal, Kalyaneswar ^{[1
,3
]}

Terechko, Valentina A. ^{[1
,3
]}

Kent, Stephen B. H. ^{[1
,2
,3
]}

机构：

[1] Univ Chicago, Inst Biophys Dynam, Chicago, IL 60637 USA

[2] Univ Chicago, Dept Chem, Chicago, IL 60637 USA

[3] Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 22期

关键词：

HIV-1; protease; Ketomethylene isostere; Aspartic proteases; Chemical protein synthesis;

D O I：

10.1016/S0960-894X(08)01314-0

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Here we report the X-ray structures of chemically synthesized HIV-1 protease and the inactive [D25N] HIV-1 protease complexed with the ketomethylene isostere inhibitor Ac-Thr-Ile-Nle psi[CO-CH2]Nle-Gln-Arg.amide at 1.4 and 1.8 angstrom resolution, respectively. In complex with the active enzyme, the keto-group was found to be converted into the hydrated gem-diol, while the structure of the complex with the inactive D25N enzyme revealed an intact keto-group. These data support the general acid-general base mechanism for HIV-1 protease catalysis. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：6012 / 6015

页数：4