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

Noske, G. D. (author)
University of São Paulo
Nakamura, A. M. (author)
University of São Paulo
Gawriljuk, V. O. (author)
University of São Paulo
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Fernandes, R. S. (author)
University of São Paulo
Lima, G. M.A. (author)
Lund University,Lunds universitet,MAX IV-laboratoriet,MAX IV Laboratory
Rosa, H. V.D. (author)
University of São Paulo
Pereira, H. D. (author)
University of São Paulo
Zeri, A. C.M. (author)
Brazilian Center For Research In Energy And Materials (CNPEM)
Nascimento, A. F.Z. (author)
Brazilian Center For Research In Energy And Materials (CNPEM)
Freire, M. C.L.C. (author)
University of São Paulo
Fearon, D. (author)
Diamond Light Source
Douangamath, A. (author)
Diamond Light Source
von Delft, F. (author)
University of Oxford,Diamond Light Source,University of Johannesburg
Oliva, G. (author)
University of São Paulo
Godoy, A. S. (author)
University of São Paulo
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 (creator_code:org_t)
Elsevier BV, 2021
2021
English.
In: Journal of Molecular Biology. - : Elsevier BV. - 0022-2836. ; 433:18
  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

Keyword

COVID
drug discovery
M
maturation
SARS-CoV-2

Publication and Content Type

art (subject category)
ref (subject category)

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