8U1V
Structure of Norovirus (Hu/GII.4/Sydney/NSW0514/2012/AU) protease in the ligand-free state
Summary for 8U1V
Entry DOI | 10.2210/pdb8u1v/pdb |
Related | 8U1W |
Descriptor | Peptidase C37 (2 entities in total) |
Functional Keywords | protease, 3-chymotrypsin-like protease, 3cl-pro, viral protein |
Biological source | Norovirus Hu/GII.4/Sydney/NSW0514/2012/AU |
Total number of polymer chains | 4 |
Total formula weight | 77321.20 |
Authors | |
Primary citation | Eruera, A.R.,McSweeney, A.M.,McKenzie-Goldsmith, G.M.,Opel-Reading, H.K.,Thomas, S.X.,Campbell, A.C.,Stubbing, L.,Siow, A.,Hubert, J.G.,Brimble, M.A.,Ward, V.K.,Krause, K.L. Crystal Structure of Inhibitor-Bound GII.4 Sydney 2012 Norovirus 3C-Like Protease. Viruses, 15:-, 2023 Cited by PubMed 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 (IC = 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. PubMed: 38005879DOI: 10.3390/v15112202 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.79 Å) |
Structure validation
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