Product release is rate-limiting for catalytic processing by the Dengue virus protease

Shannon, A. E., Pedroso, M. M., Chappell, K. J., Watterson, D., Liebscher, S., Kok, W. M., Fairlie, D. P., Schenk, G. and Young, P. R. (2016) Product release is rate-limiting for catalytic processing by the Dengue virus protease. Scientific Reports, 6 . doi:10.1038/srep37539


Author Shannon, A. E.
Pedroso, M. M.
Chappell, K. J.
Watterson, D.
Liebscher, S.
Kok, W. M.
Fairlie, D. P.
Schenk, G.
Young, P. R.
Title Product release is rate-limiting for catalytic processing by the Dengue virus protease
Journal name Scientific Reports   Check publisher's open access policy
ISSN 2045-2322
Publication date 2016-11-29
Sub-type Article (original research)
DOI 10.1038/srep37539
Open Access Status DOI
Volume 6
Total pages 11
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Abstract Dengue Virus (DENV) is the most prevalent global arbovirus, yet despite an increasing burden to health care there are currently no therapeutics available to treat infection. A potential target for antiviral drugs is the two-component viral protease NS2B-NS3pro, which is essential for viral replication. Interactions between the two components have been investigated here by probing the effect on the rate of enzyme catalysis of key mutations in a mobile loop within NS2B that is located at the interface of the two components. Steady-state kinetic assays indicated that the mutations greatly affect catalytic turnover. However, single turnover and fluorescence experiments have revealed that the mutations predominantly affect product release rather than substrate binding. Fluorescence analysis also indicated that the addition of substrate triggers a near-irreversible change in the enzyme conformation that activates the catalytic centre. Based on this mechanistic insight, we propose that residues within the mobile loop of NS2B control product release and present a new target for design of potent Dengue NS2B-NS3 protease inhibitors.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience - Publications
 
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