National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS)
Citation
Journal: Nat Commun / Year: 2021 Title: Cryo-EM structures of the SARS-CoV-2 endoribonuclease Nsp15 reveal insight into nuclease specificity and dynamics. Authors: 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 ...Authors: 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 / Robin E Stanley / 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 ...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.
History
Deposition
Sep 4, 2020
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Header (metadata) release
Dec 9, 2020
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Map release
Dec 9, 2020
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Update
Feb 17, 2021
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Current status
Feb 17, 2021
Processing site: RCSB / Status: Released
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Structure visualization
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Surface view with section colored by density value
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