Insights into the mechanism of drug resistance: X-ray structure analysis of multi-drug resistant HIV-1 protease ritonavir complex

被引：7
|
作者：
Liu, Zhigang [1 ,2 ]
Yedidi, Ravikiran S. [1 ,3 ]
Wang, Yong [1 ]
Dewdney, Tamaria G. [1 ]
Reiter, Samuel J. [1 ]
Brunzelle, Joseph S. [4 ,5 ]
Kovari, Iulia A. [1 ]
Kovari, Ladislau C. [1 ]
机构：
[1] Wayne State Univ, Dept Biochem & Mol Biol, Sch Med, Detroit, MI 48201 USA
[2] Harbor Hosp Baltimore, Div Internal Med, Baltimore, MD 21225 USA
[3] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA
[4] Northwestern Univ, Feinberg Sch Med, Life Sci Collaborat Access Team, Chicago, IL 60611 USA
[5] Northwestern Univ, Feinberg Sch Med, Dept Mol Pharmacol & Biol Chem, Chicago, IL 60611 USA
来源：
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS | 2013年 / 431卷 / 02期
基金：
美国国家卫生研究院;
关键词：
HIV-1; protease; Multi-drug resistance; X-ray crystallography; IC50; Ritonavir; INHIBITOR; REFINEMENT; MUTATIONS; VARIANT;
D O I：
10.1016/j.bbrc.2012.12.127
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Ritonavir (RTV) is a first generation HIV-1 protease inhibitor with rapidly emerging drug resistance. Mutations at residues 46, 54, 82 and 84 render the HIV-1 protease drug resistant against RTV. We report the crystal structure of multi-drug resistant (MDR) 769 HIV-1 protease (carrying resistant mutations at residues 10, 36, 46, 54, 62, 63, 71, 82, 84 and 90) complexed with RTV and the in vitro enzymatic IC50 of RTV against MDR HIV-1 protease. The structural and functional studies demonstrate significant drug resistance of MDR HIV-1 protease against RTV, arising from reduced hydrogen bonds and Van der Waals interactions between RTV and MDR HIV-1 protease. (C) 2013 Published by Elsevier Inc.
引用
收藏
页码：232 / 238
页数：7
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