6urv
Crystal structure of Yellow Fever Virus NS2B-NS3 protease domainCrystal structure of Yellow Fever Virus NS2B-NS3 protease domain
Structural highlights
FunctionA0A1W6I1A1_9FLAV Functions as a signal peptide for NS4B and is required for the interferon antagonism activity of the latter.[ARBA:ARBA00003504] Serine protease subunit NS2B: Required cofactor for the serine protease function of NS3.[PROSITE-ProRule:PRU00859] Publication Abstract from PubMedBACKGROUND: The Yellow Fever virus (YFV) is transmitted by mosquitos and causes an infection with symptoms including fever, headaches and nausea. In 20-50% of the cases, the disease may evolve to a visceral stage, reaching high mortality rates. YFV NS2B-NS3 protease has been identified as an important drug target. METHODS: Herein, we describe the crystal structure of the NS2B-NS3 protease from the 2017 YFV Brazilian circulating strain using X-ray crystallography. Furthermore, we used a combination of biochemical and biophysical assays to characterize the enzyme and investigate the impact of the polymorphisms observed in different YFV circulating strains. RESULTS: Surprisingly, the crystal structure of YFV protease seems to adopt the closed conformation without the presence of a binding partner. Although D88E and K121R mutants exhibited a lower affinity for the substrate, both revealed to be more processive, resulting in a similar catalytic efficiency in relation to the WT protease. Still, both mutants showed an accentuated decrease in stability when compared with the WT. CONCLUSIONS: The crystal structure of YFV NS2B-NS3 in closed conformation might be an important tool for the development of new drugs, as well as understanding the activation mechanism of viral proteases. Biochemical analyses indicate that the NS2B-NS3 protease of the circulating strain of YFV is more stable than previous strains. GENERAL SIGNIFICANCE: The YFV NS2B-NS3 protease is the first flaviviral structure described in its closed conformation when in a free form, implying that external factors might induce the activation of the enzyme. Structural characterization and polymorphism analysis of the NS2B-NS3 protease from the 2017 Brazilian circulating strain of Yellow Fever virus.,Noske GD, Gawriljuk VO, Fernandes RS, Furtado ND, Bonaldo MC, Oliva G, Godoy AS Biochim Biophys Acta Gen Subj. 2020 Jan 10;1864(4):129521. doi:, 10.1016/j.bbagen.2020.129521. PMID:31931019[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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