Highly Drug-Resistant HIV-1 Protease Mutant PRS17 Shows Enhanced Binding to Substrate Analogues.

ABSTRACT: We report the structural analysis of highly drug-resistant human immunodeficiency virus protease (PR) variant PR^S17, rationally selected by machine learning, in complex with substrate analogues. Crystal structures were solved of inhibitor-free inactive PR^S17-D25N, wild-type PR/CA-p2 complex, and PR^S17 in complex with substrate analogues, CA-p2 and p2-NC. Peptide analogues p2-NC and CA-p2 exhibit inhibition constants of 514 and 22 nM, respectively, for PR^S17 or approximately 3-fold better than for PR. CA-p2 is a better inhibitor of PR^S17 than are clinical inhibitors (K _i = 50-8390 nM) except for amprenavir (K _i = 11 nM). G48V resistance mutation induces curled flap tips in PR^S17-D25N struct

SUBMITTER: Agniswamy J 

PROVIDER: S-EPMC6545544 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature