6O54
Crystal Structure of multi-drug resistant HIV-1 protease PR-S17 (D25N)
Summary for 6O54
| Entry DOI | 10.2210/pdb6o54/pdb |
| Related | 5T2E |
| Descriptor | HIV-1 protease, CHLORIDE ION (3 entities in total) |
| Functional Keywords | hiv protease, hydrolase, viral protein |
| Biological source | Human immunodeficiency virus 1 |
| Total number of polymer chains | 1 |
| Total formula weight | 10932.42 |
| Authors | Wang, Y.-F.,Brothers, R.,Agniswamy, J.,Weber, I.T. (deposition date: 2019-03-01, release date: 2019-06-19, Last modification date: 2023-10-11) |
| Primary citation | Agniswamy, J.,Kneller, D.W.,Brothers, R.,Wang, Y.F.,Harrison, R.W.,Weber, I.T. Highly Drug-Resistant HIV-1 Protease Mutant PRS17 Shows Enhanced Binding to Substrate Analogues. Acs Omega, 4:8707-8719, 2019 Cited by PubMed Abstract: We report the structural analysis of highly drug-resistant human immunodeficiency virus protease (PR) variant PR, rationally selected by machine learning, in complex with substrate analogues. Crystal structures were solved of inhibitor-free inactive PR-D25N, wild-type PR/CA-p2 complex, and PR 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 or approximately 3-fold better than for PR. CA-p2 is a better inhibitor of PR than are clinical inhibitors ( = 50-8390 nM) except for amprenavir ( = 11 nM). G48V resistance mutation induces curled flap tips in PR-D25N structure. The inner P2-P2' residues of substrate analogues in PR 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 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 with substrate analogues agrees with their relative inhibition, suggesting that this mutant improves substrate binding while decreasing affinity for clinical inhibitors. PubMed: 31172041DOI: 10.1021/acsomega.9b00683 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.21 Å) |
Structure validation
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