Produção Nacional
Revisado por pares
A Crystallographic Snapshot of SARS-CoV-2 Main Protease Maturation Process
2021; Elsevier BV; Volume: 433; Issue: 18 Linguagem: Inglês
10.1016/j.jmb.2021.167118
ISSN1089-8638
AutoresG.D. Noske, A.M. Nakamura, Victor O. Gawriljuk, R.S. Fernandes, G.M.A. Lima, Higor Vinícius Dias Rosa, H.M. Pereira, Ana Carolina de Mattos Zeri, Andrey Fabricio Ziem Nascimento, Marjorie Caroline Liberato Cavalcanti Freire, D. Fearon, A. Douangamath, F. von Delft, Glaucius Oliva, André S. Godoy,
Tópico(s)RNA and protein synthesis mechanisms
ResumoSARS-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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