Mutagenesis of the West Nile virus NS2B cofactor domain reveals two regions essential for protease activity

Chappell, Keith J., Stoermer, Martin J., Fairlie, David P. and Young, Paul R. (2008) Mutagenesis of the West Nile virus NS2B cofactor domain reveals two regions essential for protease activity. Journal of General Virology, 89 4: 1010-1014. doi:10.1099/vir.0.83447-0


Author Chappell, Keith J.
Stoermer, Martin J.
Fairlie, David P.
Young, Paul R.
Title Mutagenesis of the West Nile virus NS2B cofactor domain reveals two regions essential for protease activity
Journal name Journal of General Virology   Check publisher's open access policy
ISSN 0022-1317
Publication date 2008-04-01
Year available 2008
Sub-type Article (original research)
DOI 10.1099/vir.0.83447-0
Open Access Status Not yet assessed
Volume 89
Issue 4
Start page 1010
End page 1014
Total pages 5
Place of publication Reading, England
Publisher Society for General Microbiolgoy
Language eng
Subject C1
060506 Virology
060107 Enzymes
110309 Infectious Diseases
920412 Preventive Medicine
970106 Expanding Knowledge in the Biological Sciences
Abstract The flavivirus NS2B/NS3 protease has received considerable attention as a target for the development of antiviral compounds. While substrate based inhibitors have been the primary focus to date, an approach focussing on NS2B cofactor displacement could prove to be an effective alternative. To understand better the role of the NS2B cofactor in protease activation, we conducted an alanine mutagenesis screen throughout the 42-residue central cofactor domain (NS2B(51-92)) of West Nile virus (WNV). Two sites critical for proteolytic activity were identified (NS2B(59-62) and NS2B(75-87)), where the majority of substitutions were found to significantly decrease proteolytic activity of a recombinant WNV NS2B/NS3 protease. These findings provide mechanistic insights into the structural and functional role that the cofactor may play in the substrate-bound and free protease complexes as well as providing novel sites for targeting new antiviral inhibitors.
Formatted abstract
The flavivirus NS2B/NS3 protease has received considerable attention as a target for the development of antiviral compounds. While substrate based inhibitors have been the primary focus to date, an approach focussing on NS2B cofactor displacement could prove to be an effective alternative. To understand better the role of the NS2B cofactor in protease activation, we conducted an alanine mutagenesis screen throughout the 42-residue central cofactor domain (NS2B51–92) of West Nile virus (WNV). Two sites critical for proteolytic activity were identified (NS2B59–62 and NS2B75–87), where the majority of substitutions were found to significantly decrease proteolytic activity of a recombinant WNV NS2B/NS3 protease. These findings provide mechanistic insights into the structural and functional role that the cofactor may play in the substrate-bound and free protease complexes as well as providing novel sites for targeting new antiviral inhibitors.
Keyword Yellow-fever Virus
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Supplementary material is available with the online version of this paper via the publisher.

 
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Created: Fri, 20 Mar 2009, 23:05:25 EST by Jennifer Falknau on behalf of School of Chemistry & Molecular Biosciences