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Crystal Structure of Inhibitor-Bound GII.4 Sydney 2012 Norovirus 3C-Like Protease

Authors :
Alice-Roza Eruera
Alice M. McSweeney
Geena M. McKenzie-Goldsmith
Helen K. Opel-Reading
Simone X. Thomas
Ashley C. Campbell
Louise Stubbing
Andrew Siow
Jonathan G. Hubert
Margaret A. Brimble
Vernon K. Ward
Kurt L. Krause
Source :
Viruses, Vol 15, Iss 11, p 2202 (2023)
Publication Year :
2023
Publisher :
MDPI AG, 2023.

Abstract

Norovirus is the leading cause of viral gastroenteritis worldwide, and there are no approved vaccines or therapeutic treatments for chronic or severe norovirus infections. The structural characterisation of the norovirus protease and drug development has predominantly focused upon GI.1 noroviruses, despite most global outbreaks being caused by GII.4 noroviruses. Here, we determined the crystal structures of the GII.4 Sydney 2012 ligand-free norovirus protease at 2.79 Å and at 1.83 Å with a covalently bound high-affinity (IC50 = 0.37 µM) protease inhibitor (NV-004). We show that the active sites of the ligand-free protease structure are present in both open and closed conformations, as determined by their Arg112 side chain orientation. A comparative analysis of the ligand-free and ligand-bound protease structures reveals significant structural differences in the active site cleft and substrate-binding pockets when an inhibitor is covalently bound. We also report a second molecule of NV-004 non-covalently bound within the S4 substrate binding pocket via hydrophobic contacts and a water-mediated hydrogen bond. These new insights can guide structure-aided drug design against the GII.4 genogroup of noroviruses.

Details

Language :
English
ISSN :
19994915
Volume :
15
Issue :
11
Database :
Directory of Open Access Journals
Journal :
Viruses
Publication Type :
Academic Journal
Accession number :
edsdoj.86ca3c78c4f045989589594a543e6b57
Document Type :
article
Full Text :
https://doi.org/10.3390/v15112202