Structure of West Nile virus NS3 protease: Ligand stabilization of the catalytic conformation

Robin, Gautier, Chappell, Keith, Stoermer, Martin J., Hu, Shu-Hong, Young, Paul R., Fairlie, David P. and Martin, Jennifer L. (2009) Structure of West Nile virus NS3 protease: Ligand stabilization of the catalytic conformation. Journal of Molecular Biology, 385 5: 1568-1577. doi:10.1016/j.jmb.2008.11.026

Author Robin, Gautier
Chappell, Keith
Stoermer, Martin J.
Hu, Shu-Hong
Young, Paul R.
Fairlie, David P.
Martin, Jennifer L.
Title Structure of West Nile virus NS3 protease: Ligand stabilization of the catalytic conformation
Journal name Journal of Molecular Biology   Check publisher's open access policy
ISSN 0022-2836
Publication date 2009-02-06
Year available 2008
Sub-type Article (original research)
DOI 10.1016/j.jmb.2008.11.026
Volume 385
Issue 5
Start page 1568
End page 1577
Total pages 10
Editor Peter Wright
Place of publication Oxford, U.K.
Publisher Elsevier
Language eng
Subject 030403 Characterisation of Biological Macromolecules
920109 Infectious Diseases
060199 Biochemistry and Cell Biology not elsewhere classified
Abstract Over the last decade, West Nile virus has spread rapidly via mosquito transmission from infected migratory birds to humans. One potential therapeutic approach to treating infection is to inhibit the virally encoded serine protease that is essential for viral replication. Here we report the crystal structure of the viral NS3 protease tethered to its essential NS2B cofactor and bound to a potent substrate-based tripeptide inhibitor, 2-naphthoyl-Lys-Lys-Arg-H (Ki = 41 nM), capped at the N-terminus by 2-naphthoyl and capped at the C-terminus by aldehyde. An important and unexpected feature of this structure is the presence of two conformations of the catalytic histidine suggesting a role for ligand stabilization of the catalytically competent His conformation. Analysis of other West Nile virus NS3 protease structures and related serine proteases supports this hypothesis, suggesting that the common catalytic mechanism involves an induced-fit mechanism. Crown copyright © 2008 Published by Elsevier Ltd.
Keyword West Nile virus
NS3 protease
Trypsin-like serine protease
Protease inhibitor
Crystal structure
Alpha-lytic protease
Q-Index Code C1
Q-Index Status Provisional Code
Additional Notes Available online 25 November 2008.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
Institute for Molecular Bioscience - Publications
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Created: Thu, 03 Sep 2009, 08:28:54 EST by Mr Andrew Martlew on behalf of Institute for Molecular Bioscience