Structure of the CCR5 Chemokine Receptor-HIV Entry Inhibitor Maraviroc Complex

被引：542

作者：

Tan, Qiuxiang ^{[1
]}

Zhu, Ya ^{[1
]}

Li, Jian ^{[1
]}

Chen, Zhuxi ^{[2
]}

Han, Gye Won ^{[3
]}

Kufareva, Irina ^{[4
]}

Li, Tingting ^{[1
]}

Ma, Limin ^{[1
]}

Fenalti, Gustavo ^{[3
]}

Li, Jing ^{[1
]}

Zhang, Wenru ^{[1
]}

Xie, Xin ^{[1
]}

Yang, Huaiyu ^{[2
]}

Jiang, Hualiang ^{[2
]}

Cherezov, Vadim ^{[3
]}

Liu, Hong ^{[1
]}

Stevens, Raymond C. ^{[1
,3
,5
]}

Zhao, Qiang ^{[1
]}

Wu, Beili ^{[1
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China

[3] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA

[4] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA

[5] ShanghaiTech Univ, iHuman Inst, Shanghai 201203, Peoples R China

来源：

SCIENCE | 2013年 / 341卷 / 6152期

基金：

美国国家科学基金会;

关键词：

CRYSTAL-STRUCTURE; SMALL-MOLECULE; CORECEPTOR; BINDING; DISCOVERY; TERMINUS; ANTIBODY;

D O I：

10.1126/science.1241475

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 CCR5 chemokine receptor acts as a co-receptor for HIV-1 viral entry. Here we report the 2.7 angstrom-resolution crystal structure of human CCR5 bound to the marketed HIV drug maraviroc. The structure reveals a ligand-binding site that is distinct from the proposed major recognition sites for chemokines and the viral glycoprotein gp120, providing insights into the mechanism of allosteric inhibition of chemokine signaling and viral entry. A comparison between CCR5 and CXCR4 crystal structures, along with models of co-receptor-gp120-V3 complexes, suggests that different charge distributions and steric hindrances caused by residue substitutions may be major determinants of HIV-1 co-receptor selectivity. These high-resolution insights into CCR5 can enable structure-based drug discovery for the treatment of HIV-1 infection.

引用

页码：1387 / 1390

页数：4

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