6b6i
2.4A resolution structure of human Norovirus GII.4 protease
Structural highlights
FunctionA0A0K2E2J2_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 acute gastroenteritis worldwide with a yearly reported 700 million cases driving a $60 billion global socioeconomic burden. With no FDA approved therapeutics and the chance for severe chronic infection and life-threatening complications, researchers have identified the protease as a potential target. However, drug development has focused on the norovirus GI.1 strain despite its accounting for less than 5% of all outbreaks. Our lab aims to change focus for norovirus drug design from GI.1 to the highly infective GII.4; responsible for more than 50% of all outbreaks worldwide. With the first published crystal structure of the norovirus GII.4 protease, we have identified several significant differences in the structure and active site that have hindered development of a potent inhibitor targeting the norovirus GII.4 protease. With these new insights, we have begun designing compounds that demonstrate increased inhibition of the clinically most relevant norovirus GII.4 strain. Structural and antiviral studies of the human norovirus GII.4 protease.,Muzzarelli KM, Kuiper BD, Spellmon N, Brunzelle JS, Hackett J, Amblard F, Zhou S, Liu P, Kovari IA, Yang Z, Schinazi RF, Kovari LC Biochemistry. 2019 Jan 3. doi: 10.1021/acs.biochem.8b01063. PMID:30605321[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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