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

[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.•Descr...

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Veröffentlicht in:Journal of molecular biology 2021-09, Vol.433 (18), p.167118-167118, Article 167118
Hauptverfasser: 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.
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Sprache:eng
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Zusammenfassung:[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.
ISSN:0022-2836
1089-8638
DOI:10.1016/j.jmb.2021.167118