Journal
IUCRJ
Volume 8, Issue -, Pages 973-979Publisher
INT UNION CRYSTALLOGRAPHY
DOI: 10.1107/S2052252521010113
Keywords
SARS-CoV-2; 3CL protease; main protease; catalytic mechanism; C145A mutant; enzyme-substrate complex; room-temperature X-ray crystallography
Funding
- DOE Office of Science through the National Virtual Biotechnology Laboratory (NVBL)
- Coronavirus CARES Act
- Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH
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SARS-CoV-2 main protease (M-pro) is essential for viral replication and serves as a crucial drug target. The study provides insights into the catalytic mechanism of M-pro and demonstrates that the catalytic site is pre-organized for catalysis before substrate binding. This structure is ideal for in silico modeling of the SARS-CoV-2 M-pro catalytic mechanism.
SARS-CoV-2 emerged at the end of 2019 to cause an unprecedented pandemic of the deadly respiratory disease COVID-19 that continues to date. The viral main protease (M-pro) is essential for SARS-CoV-2 replication and is therefore an important drug target. Understanding the catalytic mechanism of Mpro, a cysteine protease with a catalytic site comprising the noncanonical Cys145-His41 dyad, can help in guiding drug design. Here, a 2.0 angstrom resolution roomtemperature X-ray crystal structure is reported of a Michaelis-like complex of M-pro harboring a single inactivating mutation C145A bound to the octapeptide Ac-SAVLQSGF-CONH2 corresponding to the nsp4/nsp5 autocleavage site. The peptide substrate is unambiguously defined in subsites S5 to S3' by strong electron density. Superposition of the Michaelis-like complex with the neutron structure of substrate-free M-pro demonstrates that the catalytic site is inherently pre-organized for catalysis prior to substrate binding. Induced fit to the substrate is driven by P1 Gln binding in the predetermined subsite S1 and rearrangement of subsite S2 to accommodate P2 Leu. The Michaelis-like complex structure is ideal for in silico modeling of the SARS-CoV-2 M-pro catalytic mechanism.
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