6OTG

HIV-1 protease triple mutants V32I, I47V, V82I with GRL-011-11A (a methylamine bis-Tetrahydrofuran P2-Ligand, sulfonamide isostere derivate)

6OTG の概要

• エントリーDOI: 10.2210/pdb6otg/pdb
• 関連するPDBエントリー: 2IEN 3S54 5BRY
• 分子名称: Protease, FORMIC ACID, (3R,3aS,4R,6aR)-4-(methylamino)hexahydrofuro[2,3-b]furan-3-yl [(2S,3R)-3-hydroxy-4-{[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino}-1-phenylbutan-2-yl]carbamate, ... (5 entities in total)
• 機能のキーワード: hiv-1 protease; antiviral inhibitors; drug resistance; x-ray crystallography, hydrolase-hydrolase inhibitor complex, hydrolase/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: 22377.32

構造登録者

Wang, Y.-F.,Pawar, S.,Weber, I.T. (登録日: 2019-05-03, 公開日: 2019-05-29, 最終更新日: 2023-10-11)

主引用文献

Pawar, S.,Wang, Y.F.,Wong-Sam, A.,Agniswamy, J.,Ghosh, A.K.,Harrison, R.W.,Weber, I.T.
Structural studies of antiviral inhibitor with HIV-1 protease bearing drug resistant substitutions of V32I, I47V and V82I.
Biochem.Biophys.Res.Commun., 514:974-978, 2019

PubMed Abstract: HIV-1 protease inhibitors are effective in HIV/AIDS therapy, although drug resistance is a severe problem. This study examines the effects of four investigational inhibitors against HIV-1 protease with drug resistant mutations of V32I, I47V and V82I (PR) that model the inhibitor-binding site of HIV-2 protease. These inhibitors contain diverse chemical modifications on the darunavir scaffold and form new interactions with wild type protease, however, the measured inhibition constants for PR mutant range from 17 to 40 nM or significantly worse than picomolar values reported for wild type enzyme. The X-ray crystal structure of PR mutant in complex with inhibitor 1 at 1.5 Å resolution shows minor changes in interactions with inhibitor compared with the corresponding wild type PR complex. Instead, the basic amine at P2 of inhibitor together with mutation V82I induces two alternate conformations for the side chain of Arg8 with new interactions with inhibitor and Leu10. Hence, inhibition is influenced by small coordinated changes in hydrophobic interactions.

PubMed: 31092330
DOI: 10.1016/j.bbrc.2019.05.064

実験手法

X-RAY DIFFRACTION (1.5 Å)