2F8G

HIV-1 protease mutant I50V complexed with inhibitor TMC114

2F8G の概要

• エントリーDOI: 10.2210/pdb2f8g/pdb
• 関連するPDBエントリー: 2F80 2F81
• 分子名称: POL POLYPROTEIN, SODIUM ION, CHLORIDE ION, ... (7 entities in total)
• 機能のキーワード: hiv-1 protease-inhibitor complex, hydrolase
• 由来する生物種: Human immunodeficiency virus 1
• 細胞内の位置: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P04587
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22307.06

構造登録者

Kovalevsky, A.Y.,Weber, I.T. (登録日: 2005-12-02, 公開日: 2006-03-07, 最終更新日: 2024-02-14)

主引用文献

Kovalevsky, A.Y.,Tie, Y.,Liu, F.,Boross, P.I.,Wang, Y.F.,Leshchenko, S.,Ghosh, A.K.,Harrison, R.W.,Weber, I.T.
Effectiveness of Nonpeptide Clinical Inhibitor TMC-114 on HIV-1 Protease with Highly Drug Resistant Mutations D30N, I50V, and L90M.
J.Med.Chem., 49:1379-1387, 2006

PubMed Abstract: The potent new antiviral inhibitor TMC-114 (UIC-94017) of HIV-1 protease (PR) has been studied with three PR variants containing single mutations D30N, I50V, and L90M, which provide resistance to the major clinical inhibitors. The inhibition constants (K(i)) of TMC-114 for mutants PR(D30N), PR(I50V), and PR(L90M) were 30-, 9-, and 0.14-fold, respectively, relative to wild-type PR. The molecular basis for the inhibition was analyzed using high-resolution (1.22-1.45 A) crystal structures of PR mutant complexes with TMC-114. In PR(D30N), the inhibitor has a water-mediated interaction with the side chain of Asn30 rather than the direct interaction observed in PR, which is consistent with the relative inhibition. Similarly, in PR(I50V) the inhibitor loses favorable hydrophobic interactions with the side chain of Val50. TMC-114 has additional van der Waals contacts in PR(L90M) structure compared to the PR structure, leading to a tighter binding of the inhibitor. The observed changes in PR structure and activity are discussed in relation to the potential for development of resistant mutants on exposure to TMC-114.

PubMed: 16480273
DOI: 10.1021/jm050943c

実験手法

X-RAY DIFFRACTION (1.22 Å)