7MYY

Crystal Structure of HIV-1 PRS17 with GRL-142

7MYY の概要

• エントリーDOI: 10.2210/pdb7myy/pdb
• 分子名称: Protease, (3S,3aR,5R,7aS,8S)-hexahydro-4H-3,5-methanofuro[2,3-b]pyran-8-yl [(2S,3R)-4-[{[2-(cyclopropylamino)-1,3-benzothiazol-6-yl]sulfonyl}(2-methylpropyl)amino]-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl]carbamate, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: hiv-1 protease, multi drug resistant, hydrolase inhibitor complex, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Human immunodeficiency virus 1
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22511.75

構造登録者

Agniswamy, J.,Weber, I.T. (登録日: 2021-05-22, 公開日: 2021-07-28, 最終更新日: 2023-10-18)

主引用文献

Agniswamy, J.,Kneller, D.W.,Ghosh, A.K.,Weber, I.T.
Novel HIV PR inhibitors with C4-substituted bis-THF and bis-fluoro-benzyl target the two active site mutations of highly drug resistant mutant PR S17 .
Biochem.Biophys.Res.Commun., 566:30-35, 2021

PubMed Abstract: The emergence of multidrug resistant (MDR) HIV strains severely reduces the effectiveness of antiretroviral therapy. Clinical inhibitor darunavir (1) has picomolar binding affinity for HIV-1 protease (PR), however, drug resistant variants like PR show poor inhibition by 1, despite the presence of only two mutated residues in the inhibitor-binding site. Antiviral inhibitors that target MDR proteases like PR would be valuable as therapeutic agents. Inhibitors 2 and 3 derived from 1 through substitutions at P1, P2 and P2' positions exhibit 3.4- to 500-fold better inhibition than clinical inhibitors for PR with the exception of amprenavir. Crystal structures of PR/2 and PR/3 reveal how these inhibitors target the two active site mutations of PR. The substituted methoxy P2 group of 2 forms new interactions with G48V mutation, while the modified bis-fluoro-benzyl P1 group of 3 forms a halogen interaction with V82S mutation, contributing to improved inhibition of PR.

PubMed: 34111669
DOI: 10.1016/j.bbrc.2021.05.094

実験手法

X-RAY DIFFRACTION (1.5 Å)