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Title: X-ray structure at 1.75 resolution of a norovirus 3C protease linked to an active site-directed peptide inhibitor

Abstract

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.

Authors:
 [1];  [2];  [1]
  1. University of Southampton, England
  2. ORNL
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1033973
DOE Contract Number:  
DE-AC05-00OR22725
Resource Type:
Journal Article
Journal Name:
Journal of Molecular Biology
Additional Journal Information:
Journal Volume: 1; Journal Issue: 1; Journal ID: ISSN 0022-2836
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; CLEAVAGE; CYSTEINE; EPIDEMIOLOGY; FUNCTIONALS; GASTROINTESTINAL TRACT; PEPTIDES; PROTEINS; RESOLUTION; SUBSTRATES; VIRUSES

Citation Formats

Cooper, Jon, Coates, Leighton, and Hussey, Robert. X-ray structure at 1.75 resolution of a norovirus 3C protease linked to an active site-directed peptide inhibitor. United States: N. p., 2010. Web.
Cooper, Jon, Coates, Leighton, & Hussey, Robert. X-ray structure at 1.75 resolution of a norovirus 3C protease linked to an active site-directed peptide inhibitor. United States.
Cooper, Jon, Coates, Leighton, and Hussey, Robert. 2010. "X-ray structure at 1.75 resolution of a norovirus 3C protease linked to an active site-directed peptide inhibitor". United States.
@article{osti_1033973,
title = {X-ray structure at 1.75 resolution of a norovirus 3C protease linked to an active site-directed peptide inhibitor},
author = {Cooper, Jon and Coates, Leighton and Hussey, Robert},
abstractNote = {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.},
doi = {},
url = {https://www.osti.gov/biblio/1033973}, journal = {Journal of Molecular Biology},
issn = {0022-2836},
number = 1,
volume = 1,
place = {United States},
year = {Fri Jan 01 00:00:00 EST 2010},
month = {Fri Jan 01 00:00:00 EST 2010}
}