A Structural Study of Norovirus 3C Protease Specificity: Binding of a Designed Active Site-Directed Peptide Inhibitor

Noroviruses are the major cause of human epidemic nonbacterial gastroenteritis. Viral replication requires a 3C cysteine protease that cleaves a 200 kDa viral polyprotein into its constituent functional proteins. Here we describe the X-ray structure of the Southampton norovirus 3C protease (SV3CP) b...

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Bibliographic Details
Published in:Biochemistry (Easton) 2011-01, Vol.50 (2), p.240-249
Main Authors: Hussey, Robert J, Coates, Leighton, Gill, Raj S, Erskine, Peter T, Coker, Shu-Fen, Mitchell, Ed, Cooper, Jonathan B, Wood, Steve, Broadbridge, Robert, Clarke, Ian N, Lambden, Paul R, Shoolingin-Jordan, Peter M
Format: Article
Language:English
Subjects:
3C Viral Proteases
Amino Acid Sequence
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Caliciviridae Infections - drug therapy
Caliciviridae Infections - enzymology
Catalytic Domain - drug effects
Crystallography, X-Ray
Cysteine Endopeptidases - chemistry
Cysteine Endopeptidases - metabolism
Humans
Models, Molecular
Molecular Sequence Data
Norovirus - chemistry
Norovirus - drug effects
Norovirus - enzymology
Peptides - chemistry
Peptides - pharmacology
Protease Inhibitors - chemistry
Protease Inhibitors - pharmacology
Protein Structure, Tertiary
Sequence Alignment
Substrate Specificity
Viral Proteins - antagonists & inhibitors
Viral Proteins - chemistry
Viral Proteins - metabolism
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Summary:Noroviruses are the major cause of human epidemic nonbacterial gastroenteritis. Viral replication requires a 3C cysteine protease that cleaves a 200 kDa viral polyprotein into its constituent functional proteins. Here we describe the X-ray structure of the Southampton norovirus 3C protease (SV3CP) bound to an active site-directed peptide inhibitor (MAPI) which has been refined at 1.7 Å resolution. The inhibitor, acetyl-Glu-Phe-Gln-Leu-Gln-X, which is based on the most rapidly cleaved recognition sequence in the 200 kDa polyprotein substrate, reacts covalently through its propenyl ethyl ester group (X) with the active site nucleophile, Cys 139. The structure permits, for the first time, the identification of substrate recognition and binding groups in a noroviral 3C protease and thus provides important new information for the development of antiviral prophylactics.
ISSN:0006-2960
1520-4995
DOI:10.1021/bi1008497