4FL8

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

4FL8 の概要

• エントリーDOI: 10.2210/pdb4fl8/pdb
• 関連するPDBエントリー: 3B7V 3B80 4FLG 4FM6
• 分子名称: HIV-1 protease, heptapeptide, CHLORIDE ION, ... (6 entities in total)
• 機能のキーワード: hydrolase, catalytic mechanism, drug resistance, aspartic protease
• 由来する生物種: Human immunodeficiency virus 1 (HIV-1); 詳細
• 細胞内の位置: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P03367
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 23538.80

構造登録者

Tie, Y.F.,Shen, C.H.,Weber, I.T. (登録日: 2012-06-14, 公開日: 2012-10-17, 最終更新日: 2023-09-13)

主引用文献

Shen, C.H.,Tie, Y.,Yu, X.,Wang, Y.F.,Kovalevsky, A.Y.,Harrison, R.W.,Weber, I.T.
Capturing the Reaction Pathway in Near-Atomic-Resolution Crystal Structures of HIV-1 Protease.
Biochemistry, 51:7726-7732, 2012

PubMed Abstract: Snapshots of three consecutive steps in the proteolytic reaction of HIV-1 protease (PR) were obtained in crystal structures at resolutions of 1.2-1.4 Å. Structures of wild-type protease and two mutants (PR(V32I) and PR(I47V)) with V32I and I47V substitutions, which are common in drug resistance, reveal the gem-diol tetrahedral intermediate, the separating N- and C-terminal products, and the C-terminal product of an autoproteolytic peptide. These structures represent three stages in the reaction pathway and shed light on the reaction mechanism. The near-atomic-resolution geometric details include a short hydrogen bond between the intermediate and the outer carboxylate oxygen of one catalytic Asp25 that is conserved in all three structures. The two products in the complex with mutant PR(I47V) have a 2.2 Å separation of the amide and carboxyl carbon of the adjacent ends, suggesting partial cleavage prior to product release. The complex of mutant PR(V32I) with a single C-terminal product shows density for water molecules in the other half of the binding site, including a partial occupancy water molecule interacting with the product carboxylate end and the carbonyl oxygen of one conformation of Gly27, which suggests a potential role of Gly27 in recycling from the product complex to the ligand-free enzyme. These structural details at near-atomic resolution enhance our understanding of the reaction pathway and will assist in the design of mechanism-based inhibitors as antiviral agents.

PubMed: 22963370
DOI: 10.1021/bi3008092

実験手法

X-RAY DIFFRACTION (1.2 Å)