3U7S

HIV PR drug resistant patient's variant in complex with darunavir

「3GGT」から置き換えられました

3U7S の概要

• エントリーDOI: 10.2210/pdb3u7s/pdb
• 関連するPDBエントリー: 1GGU
• 分子名称: Pol polyprotein, (3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YL(1S,2R)-3-[[(4-AMINOPHENYL)SULFONYL](ISOBUTYL)AMINO]-1-BENZYL-2-HYDROXYPROPYLCARBAMATE, BETA-MERCAPTOETHANOL, ... (4 entities in total)
• 機能のキーワード: darunvir, resistance, mutation score, hiv protease, tmc-114, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Human immunodeficiency virus 1 (HIV-1)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22930.96

構造登録者

Saskova, K.G.,Rezacova, P.,Konvalinka, J.,Brynda, J.,Kozisek, M. (登録日: 2011-10-14, 公開日: 2012-01-18, 最終更新日: 2024-02-28)

主引用文献

Saskova, K.G.,Kozisek, M.,Rezacova, P.,Brynda, J.,Yashina, T.,Kagan, R.M.,Konvalinka, J.
Molecular characterization of clinical isolates of human immunodeficiency virus resistant to the protease inhibitor darunavir.
J.Virol., 83:8810-8818, 2009

PubMed Abstract: Darunavir is the most recently approved human immunodeficiency virus (HIV) protease (PR) inhibitor (PI) and is active against many HIV type 1 PR variants resistant to earlier-generation PIs. Darunavir shows a high genetic barrier to resistance development, and virus strains with lower sensitivity to darunavir have a higher number of PI resistance-associated mutations than viruses resistant to other PIs. In this work, we have enzymologically and structurally characterized a number of highly mutated clinically derived PRs with high levels of phenotypic resistance to darunavir. With 18 to 21 amino acid residue changes, the PR variants studied in this work are the most highly mutated HIV PR species ever studied by means of enzyme kinetics and X-ray crystallography. The recombinant proteins showed major defects in substrate binding, while the substrate turnover was less affected. Remarkably, the overall catalytic efficiency of the recombinant PRs (5% that of the wild-type enzyme) is still sufficient to support polyprotein processing and particle maturation in the corresponding viruses. The X-ray structures of drug-resistant PRs complexed with darunavir suggest that the impaired inhibitor binding could be explained by change in the PR-inhibitor hydrogen bond pattern in the P2' binding pocket due to a substantial shift of the aminophenyl moiety of the inhibitor. Recombinant virus phenotypic characterization, enzyme kinetics, and X-ray structural analysis thus help to explain darunavir resistance development in HIV-positive patients.

PubMed: 19535439
DOI: 10.1128/JVI.00451-09

実験手法

X-RAY DIFFRACTION (2.05 Å)