2HS1

Ultra-high resolution X-ray crystal structure of HIV-1 protease V32I mutant with TMC114 (darunavir) inhibitor

2HS1 の概要

• エントリーDOI: 10.2210/pdb2hs1/pdb
• 分子名称: HIV-1 Protease, CHLORIDE ION, (3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YL(1S,2R)-3-[[(4-AMINOPHENYL)SULFONYL](ISOBUTYL)AMINO]-1-BENZYL-2-HYDROXYPROPYLCARBAMATE, ... (5 entities in total)
• 機能のキーワード: ultra-high resolution active site surface binding site, hydrolase
• 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: 22789.23

構造登録者

Weber, I.T.,Kovalevsky, A.Y. (登録日: 2006-07-20, 公開日: 2006-10-03, 最終更新日: 2024-02-14)

主引用文献

Kovalevsky, A.Y.,Liu, F.,Leshchenko, S.,Ghosh, A.K.,Louis, J.M.,Harrison, R.W.,Weber, I.T.
Ultra-high Resolution Crystal Structure of HIV-1 Protease Mutant Reveals Two Binding Sites for Clinical Inhibitor TMC114.
J.Mol.Biol., 363:161-173, 2006

PubMed Abstract: TMC114 (darunavir) is a promising clinical inhibitor of HIV-1 protease (PR) for treatment of drug resistant HIV/AIDS. We report the ultra-high 0.84 A resolution crystal structure of the TMC114 complex with PR containing the drug-resistant mutation V32I (PR(V32I)), and the 1.22 A resolution structure of a complex with PR(M46L). These structures show TMC114 bound at two distinct sites, one in the active-site cavity and the second on the surface of one of the flexible flaps in the PR dimer. Remarkably, TMC114 binds at these two sites simultaneously in two diastereomers related by inversion of the sulfonamide nitrogen. Moreover, the flap site is shaped to accommodate the diastereomer with the S-enantiomeric nitrogen rather than the one with the R-enantiomeric nitrogen. The existence of the second binding site and two diastereomers suggest a mechanism for the high effectiveness of TMC114 on drug-resistant HIV and the potential design of new inhibitors.

PubMed: 16962136
DOI: 10.1016/j.jmb.2006.08.007

実験手法

X-RAY DIFFRACTION (0.84 Å)