4DQB

Crystal Structure of wild-type HIV-1 Protease in Complex with DRV

4DQB の概要

• エントリーDOI: 10.2210/pdb4dqb/pdb
• 関連するPDBエントリー: 4DQC 4DQE 4DQF 4DQG 4DQH
• 分子名称: Aspartyl protease, 1,2-ETHANEDIOL, (3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YL(1S,2R)-3-[[(4-AMINOPHENYL)SULFONYL](ISOBUTYL)AMINO]-1-BENZYL-2-HYDROXYPROPYLCARBAMATE, ... (6 entities in total)
• 機能のキーワード: hiv-1 protease, drug resistance, drug design, protease inhibitors, aids, aspartyl protease, hydrolase, 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: 22380.31

構造登録者

Schiffer, C.A.,Mittal, S. (登録日: 2012-02-15, 公開日: 2012-03-07, 最終更新日: 2024-02-28)

主引用文献

Mittal, S.,Cai, Y.,Nalam, M.N.,Bolon, D.N.,Schiffer, C.A.
Hydrophobic core flexibility modulates enzyme activity in HIV-1 protease.
J.Am.Chem.Soc., 134:4163-4168, 2012

PubMed Abstract: Human immunodeficiency virus Type-1 (HIV-1) protease is crucial for viral maturation and infectivity. Studies of protease dynamics suggest that the rearrangement of the hydrophobic core is essential for enzyme activity. Many mutations in the hydrophobic core are also associated with drug resistance and may modulate the core flexibility. To test the role of flexibility in protease activity, pairs of cysteines were introduced at the interfaces of flexible regions remote from the active site. Disulfide bond formation was confirmed by crystal structures and by alkylation of free cysteines and mass spectrometry. Oxidized and reduced crystal structures of these variants show the overall structure of the protease is retained. However, cross-linking the cysteines led to drastic loss in enzyme activity, which was regained upon reducing the disulfide cross-links. Molecular dynamics simulations showed that altered dynamics propagated throughout the enzyme from the engineered disulfide. Thus, altered flexibility within the hydrophobic core can modulate HIV-1 protease activity, supporting the hypothesis that drug resistant mutations distal from the active site can alter the balance between substrate turnover and inhibitor binding by modulating enzyme activity.

PubMed: 22295904
DOI: 10.1021/ja2095766

実験手法

X-RAY DIFFRACTION (1.5 Å)