1CQQ

TYPE 2 RHINOVIRUS 3C PROTEASE WITH AG7088 INHIBITOR

Summary for 1CQQ

• Entry DOI: 10.2210/pdb1cqq/pdb
• Descriptor: 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)
• Functional Keywords: viral protein, hydrolase
• Biological source: Human rhinovirus 2
• Cellular location: 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
• Total number of polymer chains: 1
• Total formula weight: 20582.34

Authors

Matthews, D.,Ferre, R.A. (deposition date: 1999-08-10, release date: 1999-09-20, Last modification date: 2024-10-30)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.85 Å)