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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

A Crystallographic Snapshot of SARS-CoV-2 Main Protease Maturation Process

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Author(s):
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Noske, G. D. [1] ; Nakamura, A. M. [1] ; Gawriljuk, V. O. [1] ; Fernandes, R. S. [1] ; Lima, G. M. A. [2, 3] ; Rosa, H. V. D. [1] ; Pereira, H. D. [1] ; Zeri, A. C. M. [4] ; Nascimento, A. F. Z. [4] ; Freire, M. C. L. C. [1] ; Fearon, D. [5, 6] ; Douangamath, A. [5, 6] ; von Delft, F. [7, 5, 6, 8] ; Oliva, G. [1] ; Godoy, A. S. [1]
Total Authors: 15
Affiliation:
[1] Univ Sao Paulo, Inst Phys Sao Carlos, Av Joao Dagnone 1100, BR-13563120 Sao Carlos - Brazil
[2] Astex Pharmaceut, 436 Cambridge Sci Pk, Milton Rd, Cambridge CB4 0QA - England
[3] Max IV Lab, BioMAX, Fotongatan 2, S-22484 Lund - Sweden
[4] Brazilian Ctr Res Energy & Mat CNPEM, Brazilian Synchrotron Light Lab LNLS, BR-13083970 Campinas, SP - Brazil
[5] Diamond Light Source Ltd, Harwell Sci & Innovat Campus, Didcot OX11 0QX, Oxon - England
[6] Res Complex & Harwell, Harwell Sci & Innovat Campu, Didcot OX11 0FA, Oxon - England
[7] Univ Johannesburg, Dept Biochem, ZA-2006 Auckland Pk - South Africa
[8] Univ Oxford, Ctr Med Discovery, Old Rd Campus, Roosevelt Dr, Headington OX3 7DQ - England
Total Affiliations: 8
Document type: Journal article
Source: Journal of Molecular Biology; v. 433, n. 18 SEP 3 2021.
Web of Science Citations: 1
Abstract

SARS-CoV-2 is the causative agent of COVID-19. The dimeric form of the viral M-pro 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 M-pro 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 M-pro. 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 M-pro 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. (C) 2021 Elsevier Ltd. All rights reserved. (AU)

FAPESP's process: 15/16811-3 - Multi-user equipament aproved in grant 2014:15546-1: crystallization robot Gryphon
Grantee:Richard Charles Garratt
Support Opportunities: Multi-user Equipment Program
FAPESP's process: 16/19712-9 - Structural characterization of Zika virus proteins and search for antiviral agents
Grantee:Andre Schutzer de Godoy
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
Grantee:Glaucius Oliva
Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC