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

Agniswamy, Johnson; Kneller, Daniel W.; Brothers, Rowan; Wang, Yuan-Fang; Harrison, Robert W.; Weber, Irene T.

doi:10.1021/acsomega.9b00683

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

Journal Article · Fri May 17 00:00:00 EDT 2019 · ACS Omega

DOI:https://doi.org/10.1021/acsomega.9b00683· OSTI ID:1523526

Agniswamy, Johnson ^[1]; Kneller, Daniel W. ^[1]; Brothers, Rowan ^[1]; Wang, Yuan-Fang ^[1]; Harrison, Robert W. ^[1]; ^[1]

Georgia State Univ., Atlanta, GA (United States)

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 structure. The inner P2–P2' residues of substrate analogues in PR^S17 complexes maintain similar conformations to those of wild-type complex, while significant conformational changes are observed in the peripheral residues P3, P4' of CA-p2 and P3, P4, and P3' of p2-NC. The loss of β-branched side chain by V82S mutation initiates a shift in 80’s loop and reshapes the S3/S3' subsite, which enhances substrate binding with new hydrogen bonds and van der Waals interactions that are absent in the wild-type structures. The steric hindrance caused by G48V mutation in the flap of PR^S17 contributes to altered binding interactions of P3 Arg, P4' norleucine of CA-p2, and P4 and P3' of p2-NC with the addition of new hydrogen bonds and van der Waals contacts. The enhanced interaction of PR^S17 with substrate analogues agrees with their relative inhibition, suggesting that this mutant improves substrate binding while decreasing affinity for clinical inhibitors.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: W-31109-ENG-38

OSTI ID:: 1523526

Journal Information:: ACS Omega, Journal Name: ACS Omega Journal Issue: 5 Vol. 4; ISSN 2470-1343

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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