2R38

I84V HIV-1 protease mutant in complex with a carbamoyl decorated pyrrolidine-based inhibitor

2R38 の概要

• エントリーDOI: 10.2210/pdb2r38/pdb
• 関連するPDBエントリー: 2R3T 2R3W 2R43
• 分子名称: Protease, CHLORIDE ION, 4,4'-{(3S,4S)-PYRROLIDINE-3,4-DIYLBIS[(BENZYLIMINO)SULFONYL]}DIBENZAMIDE, ... (4 entities in total)
• 機能のキーワード: protein-ligand complex, aspartyl protease, hydrolase, protease
• 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: 22298.13

構造登録者

Boettcher, J.,Blum, A.,Heine, A.,Diederich, W.E.,Klebe, G. (登録日: 2007-08-29, 公開日: 2008-09-02, 最終更新日: 2023-08-30)

主引用文献

Bottcher, J.,Blum, A.,Heine, A.,Diederich, W.E.,Klebe, G.
Structural and Kinetic Analysis of Pyrrolidine-Based Inhibitors of the Drug-Resistant Ile84Val Mutant of HIV-1 Protease
J.Mol.Biol., 383:347-357, 2008

PubMed Abstract: Human immunodeficiency virus (HIV) protease is a well-established drug target in HIV chemotherapy. However, continuously increasing resistance towards approved drugs inevitably requires the development of new inhibitors preferably showing no susceptibility against resistant HIV protease strains. Recently, symmetric pyrrolidine-3,4-bis-N-benzyl-sulfonamides have been developed as a new class of HIV-1 protease inhibitors. The most promising candidate exhibited a K(i) of 74 nM towards a wild-type protease. Herein, we report the influence of the active-site mutations Ile50Val and Ile84Val on these inhibitors by structural and kinetic analysis. Although the Ile50Val mutation leads to a significant decrease in affinity for all compounds in this series, they retain or even show increased affinity towards the important Ile84Val mutation. By detailed analysis of the crystal structures of two representatives in complex with wild-type and mutant proteases, we were able to elucidate the structural basis of this phenomenon.

PubMed: 18692068
DOI: 10.1016/j.jmb.2008.07.062

実験手法

X-RAY DIFFRACTION (1.81 Å)