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

Noske, G.D. ; Nakamura, A.M. ; Gawriljuk, V.O. ; Fernandes, R.S. ; Lima, G.M.A. ; Rosa, H.V.D. ; Pereira, H.D. ; Zeri, A.C.M. ; Nascimento, A.F.Z. ; Freire, M.C.L.C. ; Fearon, D. ; Douangamath, A. ; von Delft, F. ; Oliva, G. ; Godoy, A.S.

Journal of molecular biology, 2021-09, Vol.433 (18), p.167118-167118, Article 167118 [Periódico revisado por pares]

Netherlands: Elsevier Ltd

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  • Título:
    A Crystallographic Snapshot of SARS-CoV-2 Main Protease Maturation Process
  • Autor: Noske, G.D. ; Nakamura, A.M. ; Gawriljuk, V.O. ; Fernandes, R.S. ; Lima, G.M.A. ; Rosa, H.V.D. ; Pereira, H.D. ; Zeri, A.C.M. ; Nascimento, A.F.Z. ; Freire, M.C.L.C. ; Fearon, D. ; Douangamath, A. ; von Delft, F. ; Oliva, G. ; Godoy, A.S.
  • Assuntos: Catalytic Domain - physiology ; COVID ; Crystallography, X-Ray - methods ; Dimerization ; drug discovery ; Humans ; maturation ; Mpro ; Peptide Hydrolases - chemistry ; Peptide Hydrolases - metabolism ; SARS-CoV-2 ; SARS-CoV-2 - metabolism ; Viral Proteins - chemistry ; Viral Proteins - metabolism
  • É parte de: Journal of molecular biology, 2021-09, Vol.433 (18), p.167118-167118, Article 167118
  • Notas: ObjectType-Article-2
    SourceType-Scholarly Journals-1
    ObjectType-Feature-3
    content type line 23
    ObjectType-Review-1
    These authors contributed equally.
    Current address: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, UK.
  • Descrição: [Display omitted] •Crystal structure of the immature form of Mpro (1.6A).•Immature form of Mpro in complex with 5 fragments.•Crystal structure of Mpro C145S mutant bound to its N and C-terminals endogenous residues.•Description of the dimer-dimer intermediary formed during C-terminal cleavage.•Description of a maturation process with support of biochemical data. 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.
  • Editor: Netherlands: Elsevier Ltd
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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