Crystallographic structure of wild-type SARS-CoV-2 main protease acyl-enzyme intermediate with physiological C-terminal autoprocessing site

Jaeyong Lee, Liam J. Worrall, Marija Vuckovic, Federico I. Rosell, Francesco Gentile, Anh-Tien Ton, Nathanael A. Caveney, Fuqiang Ban, Artem Cherkasov, Mark Paetzel () and Natalie C. J. Strynadka ()
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Jaeyong Lee: The University of British Columbia
Liam J. Worrall: The University of British Columbia
Marija Vuckovic: The University of British Columbia
Federico I. Rosell: The University of British Columbia
Francesco Gentile: The University of British Columbia
Anh-Tien Ton: The University of British Columbia
Nathanael A. Caveney: The University of British Columbia
Fuqiang Ban: The University of British Columbia
Artem Cherkasov: The University of British Columbia
Mark Paetzel: Simon Fraser University
Natalie C. J. Strynadka: The University of British Columbia

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: Abstract Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the pathogen that causes the disease COVID-19, produces replicase polyproteins 1a and 1ab that contain, respectively, 11 or 16 nonstructural proteins (nsp). Nsp5 is the main protease (Mpro) responsible for cleavage at eleven positions along these polyproteins, including at its own N- and C-terminal boundaries, representing essential processing events for subsequent viral assembly and maturation. We have determined X-ray crystallographic structures of this cysteine protease in its wild-type free active site state at 1.8 Å resolution, in its acyl-enzyme intermediate state with the native C-terminal autocleavage sequence at 1.95 Å resolution and in its product bound state at 2.0 Å resolution by employing an active site mutation (C145A). We characterize the stereochemical features of the acyl-enzyme intermediate including critical hydrogen bonding distances underlying catalysis in the Cys/His dyad and oxyanion hole. We also identify a highly ordered water molecule in a position compatible for a role as the deacylating nucleophile in the catalytic mechanism and characterize the binding groove conformational changes and dimerization interface that occur upon formation of the acyl-enzyme. Collectively, these crystallographic snapshots provide valuable mechanistic and structural insights for future antiviral therapeutic development including revised molecular docking strategies based on Mpro inhibition.

Date: 2020
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DOI: 10.1038/s41467-020-19662-4

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