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A crystallographic snapshot of SARS-CoV-2 main protease maturation process

DOI: 10.1016/j.jmb.2021.167118 DOI Help

Authors: G. D. Noske (University of Sao Paulo) , A. M. Nakamura (University of Sao Paulo) , V. O. Gawriljuk (University of Sao Paulo) , R. S. Fernandes (University of Sao Paulo) , G. M. A. Lima (MAX IV Laboratory; Astex Pharmaceuticals) , H. V. D. Rosa (University of Sao Paulo) , H. D. Pereira (University of Sao Paulo) , A. C. M. Zeri (Brazilian Synchrotron Light Laboratory (LNLS)) , A. A. F. Z. Nascimento (Brazilian Synchrotron Light Laboratory (LNLS)) , M. C. L. C. Freire (University of Sao Paulo) , D. Fearon (Diamond Light Source; Research Complex at Harwell) , A. Douangamath (Diamond Light Source; Research Complex at Harwell) , F. Von Delft (Diamond Light Source; Research Complex at Harwell; University of Oxford; University of Johannesburg) , G. Oliva (University of Sao Paulo) , A. S. Godoy (University of Sao Paulo)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Molecular Biology

State: Published (Approved)
Published: June 2021
Diamond Proposal Number(s): 27963

Abstract: SARS-CoV-2 is the causative agent of COVID-19. The dimeric form of the viral Mpro is responsible for the cleavage of the viral polyprotein in 11 sites, including its own N and C-terminus. The lack of structural information for intermediary forms of Mpro is a setback for the understanding its self-maturation process. Herein, we used X-ray crystallography combined with biochemical data to characterize multiple forms of SARS-CoV-2 Mpro. For the immature form, we show that extra N-terminal residues caused conformational changes in the positioning of domain-three over the active site, hampering the dimerization and diminishing its activity. We propose that this form preludes the cis and trans-cleavage of N-terminal residues. Using fragment screening, we probe new cavities in this form which can be used to guide therapeutic development. Furthermore, we characterized a serine site-directed mutant of the Mpro bound to its endogenous N and C-terminal residues during dimeric association stage of the maturation process. We suggest this form is a transitional state during the C-terminal trans-cleavage. This data sheds light in the structural modifications of the SARS-CoV-2 main protease during its self-maturation process.

Journal Keywords: SARS-CoV-2; COVID; Mpro; maturation; drug discovery

Diamond Keywords: COVID-19; Viruses; Enzymes

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

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: MANACA at SIRIUS

Added On: 28/06/2021 08:57

Discipline Tags:

Catalysis Life Sciences & Biotech Health & Wellbeing Drug Discovery Infectious Diseases Pathogens Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)