Structural dynamics of Zika virus NS2B-NS3 protease binding to dipeptide inhibitors

Page view(s)
5
Checked on Feb 06, 2024
Structural dynamics of Zika virus NS2B-NS3 protease binding to dipeptide inhibitors
Title:
Structural dynamics of Zika virus NS2B-NS3 protease binding to dipeptide inhibitors
Journal Title:
Structure
Publication Date:
06 July 2017
Citation:
Abstract:
The NS2B-NS3 viral protease is an attractive drug target against Zika virus (ZIKV) due to its importance in viral replication and maturation. Here we report the crystal structure of protease in complex with a dipeptide inhibitor – Acyl-KR-aldehyde (compound 1). The aldehyde moiety forms a covalent bond with the catalytic Ser135 of NS3. The Arg and Lys residues in the inhibitor occupy the S1 and S2 sites of the protease respectively. NMR studies demonstrate that the complex is in the closed conformation in solution. The chemical environment of residues surrounding the active site is sensitive to the bound inhibitor as demonstrated by the comparison with two other non-covalent dipeptides – Acyl-K-Agmatine (compound 2) and Acyl-KR-COOH (compound 3). Removing the aldehyde moiety in 1 converts the binding mode from slow to fast exchange regime. The structural dynamics information obtained in this study will guide future drug discovery against ZIKV and other flaviviruses.
License type:
PublisherCopyrights
Funding Info:
(1) Start-up grant from Lee Kong Chian School of Medicine, Nanyang Technological University, (2) National Medical Research Council grant CBRG15May045, (3) National Research Foundation grant NRF2016NRF-CRP001-063, (4) A*STAR JCO grant (1431AFG102/1331A028).
Description:
ISSN:
0969-2126
1878-4186
Files uploaded:

File Size Format Action
manuscript-li-structure-2017.docx 4.38 MB DOCX Open