8u1v
Structure of Norovirus (Hu/GII.4/Sydney/NSW0514/2012/AU) protease in the ligand-free state
Structural highlights
FunctionK4L8Z7_9CALI 3C-like protease processes the polyprotein: 3CLpro-RdRp is first released by autocleavage, then all other proteins are cleaved. May cleave polyadenylate-binding protein thereby inhibiting cellular translation.[PROSITE-ProRule:PRU00870] NTPase presumably plays a role in replication. Despite having similarities with helicases, does not seem to display any helicase activity.[ARBA:ARBA00025124] Viral genome-linked protein is covalently linked to the 5'-end of the positive-strand, negative-strand genomic RNAs and subgenomic RNA. Acts as a genome-linked replication primer. May recruit ribosome to viral RNA thereby promoting viral proteins translation.[ARBA:ARBA00025359] Publication Abstract from PubMedNorovirus 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 A and at 1.83 A with a covalently bound high-affinity (IC(50) = 0.37 microM) 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. Crystal Structure of Inhibitor-Bound GII.4 Sydney 2012 Norovirus 3C-Like Protease.,Eruera AR, McSweeney AM, McKenzie-Goldsmith GM, Opel-Reading HK, Thomas SX, Campbell AC, Stubbing L, Siow A, Hubert JG, Brimble MA, Ward VK, Krause KL Viruses. 2023 Oct 31;15(11):2202. doi: 10.3390/v15112202. PMID:38005879[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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