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

Gabriela Dias Noske, Yun Song, Rafaela Sachetto Fernandes, Rod Chalk, Haitem Elmassoudi, Lizbé Koekemoer, C. David Owen, Tarick J. El-Baba, Carol V. Robinson, Glaucius Oliva and Andre Schutzer Godoy ()
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Gabriela Dias Noske: University of Sao Paulo, Av. Joao Dagnone
Yun Song: Harwell Science and Innovation Campus
Rafaela Sachetto Fernandes: University of Sao Paulo, Av. Joao Dagnone
Rod Chalk: Oxford University
Haitem Elmassoudi: Oxford University
Lizbé Koekemoer: Oxford University
C. David Owen: Harwell Science and Innovation Campus
Tarick J. El-Baba: University of Oxford
Carol V. Robinson: University of Oxford
Glaucius Oliva: University of Sao Paulo, Av. Joao Dagnone
Andre Schutzer Godoy: University of Sao Paulo, Av. Joao Dagnone

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract The main protease from SARS-CoV-2 (Mpro) is responsible for cleavage of the viral polyprotein. Mpro self-processing is called maturation, and it is crucial for enzyme dimerization and activity. Here we use C145S Mpro 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 Å cryo-EM structure provides details of Mpro 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 Mpro dimerization is triggered by induced fit due to covalent linkage during substrate processing rather than the N-terminal processing.

Date: 2023
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DOI: 10.1038/s41467-023-37035-5

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