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Structural characterization and polymorphism analysis of the NS2B-NS3 protease from the 2017 Brazilian circulating strain of Yellow Fever virus

DOI: 10.1016/j.bbagen.2020.129521 DOI Help

Authors: Gabriela Dias Noske (Physics Institute of Sao Carlos, University of Sao Paulo) , Victor Oliveira Gawriljuk (Physics Institute of Sao Carlos, University of Sao Paulo) , Rafaela Sachetto Fernandes (Physics Institute of Sao Carlos, University of Sao Paulo) , Nathalia Dias Furtado (Instituto Oswaldo Cruz, Fundação Oswaldo Cruz) , Myrna Cristina Bonaldo (Instituto Oswaldo Cruz, Fundação Oswaldo Cruz) , Glaucius Oliva (Physics Institute of Sao Carlos, University of Sao Paulo) , Andre Godoy (Physics Institute of Sao Carlos, University of Sao Paulo)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biochimica Et Biophysica Acta (bba) - General Subjects

State: Published (Approved)
Published: January 2020
Diamond Proposal Number(s): 22129

Abstract: Background: 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.

Journal Keywords: Yellow Fever virus; Flavivirus; Protease; NS3NS2B

Diamond Keywords: Yellow Fever; Viruses

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 15/01/2020 09:07

Discipline Tags:

Pathogens Infectious Diseases Disease in the Developing World Health & Wellbeing Biochemistry Chemistry Structural biology Biophysics Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)