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The mechanisms of catalysis and ligand binding for the SARS-CoV-2 NSP3 macrodomain from neutron and x-ray diffraction at room temperature

By Galen J. Correy, Daniel W. Kneller, Gwyndalyn Phillips, Swati Pant, Silvia Russi, Aina E. Cohen, George Meigs, James Holton1, Stefan Gahbauer, Michael Thompson2, Alan Ashworth, Leighton Coates, Andrey Kovalevsky, Flora Meilleur, James Fraser3

1. University of California San Francisco 2. University of California - San Francisco 3. University of California-San Francisco

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BioXFEL Publications

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Type

journal-article

Author

Galen J. Correy and Daniel W. Kneller and Gwyndalyn Phillips and Swati Pant and Silvia Russi and Aina E. Cohen and George Meigs and James M. Holton and Stefan Gahbauer and Michael C. Thompson and Alan Ashworth and Leighton Coates and Andrey Kovalevsky and Flora Meilleur and James S. Fraser

Citation

Correy, G. J., Kneller, D. W., Phillips, G., Pant, S., Russi, S., Cohen, A. E., Meigs, G., Holton, J. M., Gahbauer, S., Thompson, M. C., Ashworth, A., Coates, L., Kovalevsky, A., Meilleur, F., & Fraser, J. S. (2022). The mechanisms of catalysis and ligand binding for the SARS-CoV-2 NSP3 macrodomain from neutron and x-ray diffraction at room temperature. Science Advances, 8(21). https://doi.org/10.1126/sciadv.abo5083

Abstract

The nonstructural protein 3 (NSP3) macrodomain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Mac1) removes adenosine diphosphate (ADP) ribosylation posttranslational modifications, playing a key role in the immune evasion capabilities of the virus responsible for the coronavirus disease 2019 pandemic. Here, we determined neutron and x-ray crystal structures of the SARS-CoV-2 NSP3 macrodomain using multiple crystal forms, temperatures, and pHs, across the apo and ADP-ribose–bound states. We characterize extensive solvation in the Mac1 active site and visualize how water networks reorganize upon binding of ADP-ribose and non-native ligands, inspiring strategies for displacing waters to increase the potency of Mac1 inhibitors. Determining the precise orientations of active site water molecules and the protonation states of key catalytic site residues by neutron crystallography suggests a catalytic mechanism for coronavirus macrodomains distinct from the substrate-assisted mechanism proposed for human MacroD2. These data provoke a reevaluation of macrodomain catalytic mechanisms and will guide the optimization of Mac1 inhibitors.

DOI

http://dx.doi.org/10.1126/sciadv.abo5083