Cryo-EM structures of the SARS-CoV-2 endoribonuclease Nsp15 reveal insight into nuclease specificity and dynamics

Monica C. Pillon (), Meredith N. Frazier, Lucas B. Dillard, Jason G. Williams, Seda Kocaman, Juno M. Krahn, Lalith Perera, Cassandra K. Hayne, Jacob Gordon, Zachary D. Stewart, Mack Sobhany, Leesa J. Deterding, Allen L. Hsu, Venkata P. Dandey, Mario J. Borgnia and Robin E. Stanley ()
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Monica C. Pillon: National Institutes of Health, Department of Health and Human Services
Meredith N. Frazier: National Institutes of Health, Department of Health and Human Services
Lucas B. Dillard: National Institutes of Health, Department of Health and Human Services
Jason G. Williams: National Institutes of Health, Department of Health and Human Services
Seda Kocaman: National Institutes of Health, Department of Health and Human Services
Juno M. Krahn: National Institutes of Health, Department of Health and Human Services
Lalith Perera: National Institutes of Health, Department of Health and Human Services
Cassandra K. Hayne: National Institutes of Health, Department of Health and Human Services
Jacob Gordon: National Institutes of Health, Department of Health and Human Services
Zachary D. Stewart: National Institutes of Health, Department of Health and Human Services
Mack Sobhany: National Institutes of Health, Department of Health and Human Services
Leesa J. Deterding: National Institutes of Health, Department of Health and Human Services
Allen L. Hsu: National Institutes of Health, Department of Health and Human Services
Venkata P. Dandey: National Institutes of Health, Department of Health and Human Services
Mario J. Borgnia: National Institutes of Health, Department of Health and Human Services
Robin E. Stanley: National Institutes of Health, Department of Health and Human Services

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Nsp15, a uridine specific endoribonuclease conserved across coronaviruses, processes viral RNA to evade detection by host defense systems. Crystal structures of Nsp15 from different coronaviruses have shown a common hexameric assembly, yet how the enzyme recognizes and processes RNA remains poorly understood. Here we report a series of cryo-EM reconstructions of SARS-CoV-2 Nsp15, in both apo and UTP-bound states. The cryo-EM reconstructions, combined with biochemistry, mass spectrometry, and molecular dynamics, expose molecular details of how critical active site residues recognize uridine and facilitate catalysis of the phosphodiester bond. Mass spectrometry revealed the accumulation of cyclic phosphate cleavage products, while analysis of the apo and UTP-bound datasets revealed conformational dynamics not observed by crystal structures that are likely important to facilitate substrate recognition and regulate nuclease activity. Collectively, these findings advance understanding of how Nsp15 processes viral RNA and provide a structural framework for the development of new therapeutics.

Date: 2021
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DOI: 10.1038/s41467-020-20608-z

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