1CQQ

TYPE 2 RHINOVIRUS 3C PROTEASE WITH AG7088 INHIBITOR

1CQQ の概要

• エントリーDOI: 10.2210/pdb1cqq/pdb
• 分子名称: TYPE 2 RHINOVIRUS 3C PROTEASE, 4-{2-(4-FLUORO-BENZYL)-6-METHYL-5-[(5-METHYL-ISOXAZOLE-3-CARBONYL)-AMINO]-4-OXO-HEPTANOYLAMINO}-5-(2-OXO-PYRROLIDIN-3-YL)-PENTANOIC ACID ETHYL ESTER (3 entities in total)
• 機能のキーワード: viral protein, hydrolase
• 由来する生物種: Human rhinovirus 2
• 細胞内の位置: Capsid protein VP0: Virion . Capsid protein VP4: Virion . Capsid protein VP2: Virion . Capsid protein VP3: Virion . Capsid protein VP1: Virion . Protein 2B: Host cytoplasmic vesicle membrane ; Peripheral membrane protein ; Cytoplasmic side . Protein 2C: Host cytoplasmic vesicle membrane ; Peripheral membrane protein ; Cytoplasmic side . Protein 3A: Host cytoplasmic vesicle membrane ; Peripheral membrane protein ; Cytoplasmic side . Protein 3AB: Host cytoplasmic vesicle membrane ; Peripheral membrane protein ; Cytoplasmic side . Viral protein genome-linked: Virion . Protease 3C: Host cytoplasm . Protein 3CD: Host cytoplasmic vesicle membrane ; Peripheral membrane protein ; Cytoplasmic side . RNA-directed RNA polymerase: Host cytoplasmic vesicle membrane ; Peripheral membrane protein ; Cytoplasmic side : P04936
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 20582.34

構造登録者

Matthews, D.,Ferre, R.A. (登録日: 1999-08-10, 公開日: 1999-09-20, 最終更新日: 2024-10-30)

主引用文献

Matthews, D.A.,Dragovich, P.S.,Webber, S.E.,Fuhrman, S.A.,Patick, A.K.,Zalman, L.S.,Hendrickson, T.F.,Love, R.A.,Prins, T.J.,Marakovits, J.T.,Zhou, R.,Tikhe, J.,Ford, C.E.,Meador, J.W.,Ferre, R.A.,Brown, E.L.,Binford, S.L.,Brothers, M.A.,DeLisle, D.M.,Worland, S.T.
Structure-assisted design of mechanism-based irreversible inhibitors of human rhinovirus 3C protease with potent antiviral activity against multiple rhinovirus serotypes.
Proc.Natl.Acad.Sci.USA, 96:11000-11007, 1999

PubMed Abstract: Human rhinoviruses, the most important etiologic agents of the common cold, are messenger-active single-stranded monocistronic RNA viruses that have evolved a highly complex cascade of proteolytic processing events to control viral gene expression and replication. Most maturation cleavages within the precursor polyprotein are mediated by rhinovirus 3C protease (or its immediate precursor, 3CD), a cysteine protease with a trypsin-like polypeptide fold. High-resolution crystal structures of the enzyme from three viral serotypes have been used for the design and elaboration of 3C protease inhibitors representing different structural and chemical classes. Inhibitors having alpha,beta-unsaturated carbonyl groups combined with peptidyl-binding elements specific for 3C protease undergo a Michael reaction mediated by nucleophilic addition of the enzyme's catalytic Cys-147, resulting in covalent-bond formation and irreversible inactivation of the viral protease. Direct inhibition of 3C proteolytic activity in virally infected cells treated with these compounds can be inferred from dose-dependent accumulations of viral precursor polyproteins as determined by SDS/PAGE analysis of radiolabeled proteins. Cocrystal-structure-assisted optimization of 3C-protease-directed Michael acceptors has yielded molecules having extremely rapid in vitro inactivation of the viral protease, potent antiviral activity against multiple rhinovirus serotypes and low cellular toxicity. Recently, one compound in this series, AG7088, has entered clinical trials.

PubMed: 10500114
DOI: 10.1073/pnas.96.20.11000

実験手法

X-RAY DIFFRACTION (1.85 Å)