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

Noske, G. D. ; Nakamura, A. M. ; Gawriljuk, V. O. ; Fernandes, R. S. ; Lima, G. M.A. LU orcid ; Rosa, H. V.D. ; Pereira, H. D. ; Zeri, A. C.M. ; Nascimento, A. F.Z. and Freire, M. C.L.C. , et al. (2021) In Journal of Molecular Biology 433(18).
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
COVID, drug discovery, M, maturation, SARS-CoV-2
in
Journal of Molecular Biology
volume
433
issue
18
article number
167118
publisher
Elsevier
external identifiers
  • scopus:85109164122
  • pmid:34174328
ISSN
0022-2836
DOI
10.1016/j.jmb.2021.167118
language
English
LU publication?
yes
id
8dbec270-c456-47ba-9016-178a2c7bf428
date added to LUP
2021-08-16 13:02:38
date last changed
2024-06-15 14:25:24
@article{8dbec270-c456-47ba-9016-178a2c7bf428,
  abstract     = {{<p>SARS-CoV-2 is the causative agent of COVID-19. The dimeric form of the viral M<sup>pro</sup> 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<sup>pro</sup> 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<sup>pro</sup>. 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<sup>pro</sup> 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.</p>}},
  author       = {{Noske, G. D. and Nakamura, A. M. and Gawriljuk, V. O. and Fernandes, R. S. and Lima, G. M.A. and Rosa, H. V.D. and Pereira, H. D. and Zeri, A. C.M. and Nascimento, A. F.Z. and Freire, M. C.L.C. and Fearon, D. and Douangamath, A. and von Delft, F. and Oliva, G. and Godoy, A. S.}},
  issn         = {{0022-2836}},
  keywords     = {{COVID; drug discovery; M; maturation; SARS-CoV-2}},
  language     = {{eng}},
  month        = {{09}},
  number       = {{18}},
  publisher    = {{Elsevier}},
  series       = {{Journal of Molecular Biology}},
  title        = {{A Crystallographic Snapshot of SARS-CoV-2 Main Protease Maturation Process : SARS-CoV-2 M<sup>pro</sup> maturation}},
  url          = {{http://dx.doi.org/10.1016/j.jmb.2021.167118}},
  doi          = {{10.1016/j.jmb.2021.167118}},
  volume       = {{433}},
  year         = {{2021}},
}