8EY2

Cryo-EM structure of SARS-CoV-2 Main protease C145S in complex with N-terminal peptide

Summary for 8EY2

• Entry DOI: 10.2210/pdb8ey2/pdb
• EMDB information: 28666
• Descriptor: 3C-like proteinase (1 entity in total)
• Functional Keywords: covid19, mpro, main protease, cryo-em, 3cl, sars-cov-2, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 4
• Total formula weight: 138269.48

Authors

Noske, G.D.,Song, Y.,Fernandes, R.S.,Oliva, G.,Godoy, A.S. (deposition date: 2022-10-26, release date: 2022-12-07, Last modification date: 2024-05-01)

Primary citation

Noske, G.D.,Song, Y.,Fernandes, R.S.,Chalk, R.,Elmassoudi, H.,Koekemoer, L.,Owen, C.D.,El-Baba, T.J.,Robinson, C.V.,Oliva, G.,Godoy, A.S.
An in-solution snapshot of SARS-COV-2 main protease maturation process and inhibition.
Nat Commun, 14:1545-1545, 2023

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

PubMed: 36941262
DOI: 10.1038/s41467-023-37035-5

Experimental method

ELECTRON MICROSCOPY (3.5 Å)