6O5A

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

(2019) ACS Omega 4: 8707-8719

• PubMed: 31172041 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1021/acsomega.9b00683
• Primary Citation of Related Structures:  
  6O48, 6O54, 6O57, 6O5A, 6O5X


• PubMed 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 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 More

---

Organizational Affiliation: 

Department of Biology, Georgia State University, P.O. Box 4010, Atlanta, Georgia 30302, United States.