X-ray structure at 1.75 resolution of a norovirus 3C protease linked to an active site-directed peptide inhibitor
- University of Southampton, England
- ORNL
Noroviruses are recognized universally as the most important cause of human epidemic non-bacterial gastroenteritis. Viral replication requires a 3C cysteine protease that cleaves a 200kDa 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 1.75 resolution, following initial MAD phasing with a selenomethionine derivative. The inhibitor, acetyl-Glu-Phe-Gln-Leu-Gln-X, based on a 3C protease cleavage recognition sequences in the 200kDa polyprotein substrate, reacts covalently through its propenylethylester group (X) with the active site nucleophile, Cys 139. The 3C protease-inhibitor structure permits, for the first time, the identification of substrate recognition and binding groups and provides important new information for the development of antiviral prophylactics.
- Research Organization:
- Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC)
- DOE Contract Number:
- DE-AC05-00OR22725
- OSTI ID:
- 1033973
- Journal Information:
- Journal of Molecular Biology, Vol. 1, Issue 1; ISSN 0022-2836
- Country of Publication:
- United States
- Language:
- English
Similar Records
Putative structural rearrangements associated with the interaction of macrocyclic inhibitors with norovirus 3CL protease
Characterization and inhibition of norovirus proteases of genogroups I and II using a fluorescence resonance energy transfer assay