A Crystallographic Snapshot of SARS-CoV-2 Main Protease Maturation Process
2021
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.
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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