6O54

Crystal Structure of multi-drug resistant HIV-1 protease PR-S17 (D25N)

6O54 の概要

• エントリーDOI: 10.2210/pdb6o54/pdb
• 関連するPDBエントリー: 5T2E
• 分子名称: HIV-1 protease, CHLORIDE ION (3 entities in total)
• 機能のキーワード: hiv protease, hydrolase, viral protein
• 由来する生物種: Human immunodeficiency virus 1
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 10932.42

構造登録者

Wang, Y.-F.,Brothers, R.,Agniswamy, J.,Weber, I.T. (登録日: 2019-03-01, 公開日: 2019-06-19, 最終更新日: 2023-10-11)

主引用文献

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

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: 31172041
DOI: 10.1021/acsomega.9b00683

実験手法

X-RAY DIFFRACTION (1.21 Å)