An in-solution snapshot of SARS-COV-2 main protease maturation process and inhibition

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Noske, Gabriela Dias ; Song, Yun ; Fernandes, Rafaela Sachetto ; Chalk, Rod ; Elmassoudi, Haitem ; Koekemoer, Lizbe ; Owen, C. David J. ; El-Baba, Tarick V. ; Robinson, Carol ; Oliva, Glaucius ; Godoy, Andre Schutzer

• Tipo de documento: Artigo Científico
• Fonte: NATURE COMMUNICATIONS; v. 14, n. 1, p. 13-pg., 2023-03-20.

Resumo

The main protease from SARS-CoV-2 (M-pro) is responsible for cleavage of the viral polyprotein. M-pro self-processing is called maturation, and it is crucial for enzyme dimerization and activity. Here we use C145S M-pro to study the structure and dynamics of N-terminal cleavage in solution. Native mass spectroscopy analysis shows that mixed oligomeric states are composed of cleaved and uncleaved particles, indicating that N-terminal processing is not critical for dimerization. A 3.5 & ANGS; cryo-EM structure provides details of M-pro N-terminal cleavage outside the constrains of crystal environment. We show that different classes of inhibitors shift the balance between oligomeric states. While non-covalent inhibitor MAT-POS-e194df51-1 prevents dimerization, the covalent inhibitor nirmatrelvir induces the conversion of monomers into dimers, even with intact N-termini. Our data indicates that the M-pro dimerization is triggered by induced fit due to covalent linkage during substrate processing rather than the N-terminal processing. The Main protease of SARS-CoV-2 is key for viral replication, but its maturation process is still not completely understood. Here, the authors not only reveal unique details from the first step of maturation, but also demonstrate how different classes of inhibitor can block this step. (AU)

• Processo FAPESP: 13/07600-3 - CIBFar - Centro de Inovação em Biodiversidade e Fármacos
• Beneficiário: Glaucius Oliva
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 16/19712-9 - Caracterização estrutural das proteínas do vírus Zika e busca por agentes antivirais
• Beneficiário: Andre Schutzer de Godoy
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado