3B7V

HIV-1 protease complexed with gem-diol-amine tetrahedral intermediate NLLTQI

3B7V の概要

• エントリーDOI: 10.2210/pdb3b7v/pdb
• 関連するPDBエントリー: 3B80
• 関連するBIRD辞書のPRD_ID: PRD_000321
• 分子名称: Protease, peptide, SODIUM ION, ... (6 entities in total)
• 機能のキーワード: hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Human immunodeficiency virus type 1 BH10; 詳細
• 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: 3
• 化学式量合計: 22421.64

構造登録者

Kovalevsky, A.Y.,Chumanevich, A.A.,Weber, I.T. (登録日: 2007-10-31, 公開日: 2007-12-18, 最終更新日: 2023-08-30)

主引用文献

Kovalevsky, A.Y.,Chumanevich, A.A.,Liu, F.,Louis, J.M.,Weber, I.T.
Caught in the Act: The 1.5 A Resolution Crystal Structures of the HIV-1 Protease and the I54V Mutant Reveal a Tetrahedral Reaction Intermediate.
Biochemistry, 46:14854-14864, 2007

PubMed Abstract: HIV-1 protease (PR) is the target for several important antiviral drugs used in AIDS therapy. The drugs bind inside the active site cavity of PR where normally the viral polyprotein substrate is bound and hydrolyzed. We report two high-resolution crystal structures of wild-type PR (PRWT) and the multi-drug-resistant variant with the I54V mutation (PRI54V) in complex with a peptide at 1.46 and 1.50 A resolution, respectively. The peptide forms a gem-diol tetrahedral reaction intermediate (TI) in the crystal structures. Distinctive interactions are observed for the TI binding in the active site cavity of PRWT and PRI54V. The mutant PRI54V/TI complex has lost water-mediated hydrogen bond interactions with the amides of Ile50 and Ile50' in the flap. Hence, the structures provide insight into the mechanism of drug resistance arising from this mutation. The structures also illustrate an intermediate state in the hydrolysis reaction. One of the gem-diol hydroxide groups in the PRWT complex forms a very short (2.3 A) hydrogen bond with the outer carboxylate oxygen of Asp25. Quantum chemical calculations based on this TI structure are consistent with protonation of the inner carboxylate oxygen of Asp25', in contrast to several theoretical studies. These TI complexes and quantum calculations are discussed in relation to the chemical mechanism of the peptide bond hydrolysis catalyzed by PR.

PubMed: 18052235
DOI: 10.1021/bi700822g

実験手法

X-RAY DIFFRACTION (1.46 Å)