Critical differences in HIV-1 and HIV-2 protease specificity for clinical inhibitors

被引:41
作者
Tie, Yunfeng [1 ]
Wang, Yuan-Fang [1 ]
Boross, Peter I. [2 ]
Chiu, Ting-Yi [1 ]
Ghosh, Arun K. [3 ]
Tozser, Jozsef [2 ]
Louis, John M. [4 ]
Harrison, Robert W. [1 ,5 ]
Weber, Irene T. [1 ,6 ]
机构
[1] Georgia State Univ, Dept Biol, Atlanta, GA 30303 USA
[2] Univ Debrecen, Fac Med, Dept Biochem & Mol Biol, Debrecen, Hungary
[3] Purdue Univ, Dept Chem & Med Chem, W Lafayette, IN 47907 USA
[4] NIDDK, Chem Phys Lab, NIH, DHHS, Bethesda, MD 20892 USA
[5] Georgia State Univ, Dept Comp Sci, Atlanta, GA 30303 USA
[6] Georgia State Univ, Dept Chem, Atlanta, GA 30303 USA
基金
美国国家卫生研究院;
关键词
HIV; AIDS; drug resistance; aspartic protease; antiviral inhibitors; molecular recognition; RESOLUTION CRYSTAL-STRUCTURES; AMINO-ACID PREFERENCES; DRUG-RESISTANT MUTANTS; RETROVIRAL PROTEASES; LIGAND SPECIFICITY; SUSCEPTIBILITY; COMPLEXES; INFECTION; SEQUENCES; MOLSCRIPT;
D O I
10.1002/pro.2019
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
Clinical inhibitor amprenavir (APV) is less effective on HIV-2 protease (PR2) than on HIV-1 protease (PR1). We solved the crystal structure of PR2 with APV at 1.5 angstrom resolution to identify structural changes associated with the lowered inhibition. Furthermore, we analyzed the PR1 mutant (PR1M) with substitutions V32I, I47V, and V82I that mimic the inhibitor binding site of PR2. PR1M more closely resembled PR2 than PR1 in catalytic efficiency on four substrate peptides and inhibition by APV, whereas few differences were seen for two other substrates and inhibition by saquinavir (SQV) and darunavir (DRV). High resolution crystal structures of PR1M with APV, DRV, and SQV were compared with available PR1 and PR2 complexes. Val/Ile32 and Ile/Val47 showed compensating interactions with SQV in PR1M and PR1, however, Ile82 interacted with a second SQV bound in an extension of the active site cavity of PR1M. Residues 32 and 82 maintained similar interactions with DRV and APV in all the enzymes, whereas Val47 and Ile47 had opposing effects in the two subunits. Significantly diminished interactions were seen for the aniline of APV bound in PR1M and PR2 relative to the strong hydrogen bonds observed in PR1, consistent with 15- and 19-fold weaker inhibition, respectively. Overall, PR1M partially replicates the specificity of PR2 and gives insight into drug resistant mutations at residues 32, 47, and 82. Moreover, this analysis provides a structural explanation for the weaker antiviral effects of APV on HIV-2.
引用
收藏
页码:339 / 350
页数:12
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