National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS)
ZIA ES103247
United States
National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS)
Z01 ES043010
United States
National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS)
1ZI CES102488
United States
National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS)
1ZI CES103206
United States
National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS)
ZIC ES103326
United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
1ZIAES103340
United States
Citation
Journal: Nucleic Acids Res / Year: 2021 Title: Characterization of SARS2 Nsp15 nuclease activity reveals it's mad about U. Authors: Meredith N Frazier / Lucas B Dillard / Juno M Krahn / Lalith Perera / Jason G Williams / Isha M Wilson / Zachary D Stewart / Monica C Pillon / Leesa J Deterding / Mario J Borgnia / Robin E Stanley / Abstract: Nsp15 is a uridine specific endoribonuclease that coronaviruses employ to cleave viral RNA and evade host immune defense systems. Previous structures of Nsp15 from across Coronaviridae revealed that ...Nsp15 is a uridine specific endoribonuclease that coronaviruses employ to cleave viral RNA and evade host immune defense systems. Previous structures of Nsp15 from across Coronaviridae revealed that Nsp15 assembles into a homo-hexamer and has a conserved active site similar to RNase A. Beyond a preference for cleaving RNA 3' of uridines, it is unknown if Nsp15 has any additional substrate preferences. Here, we used cryo-EM to capture structures of Nsp15 bound to RNA in pre- and post-cleavage states. The structures along with molecular dynamics and biochemical assays revealed critical residues involved in substrate specificity, nuclease activity, and oligomerization. Moreover, we determined how the sequence of the RNA substrate dictates cleavage and found that outside of polyU tracts, Nsp15 has a strong preference for purines 3' of the cleaved uridine. This work advances our understanding of how Nsp15 recognizes and processes viral RNA, and will aid in the development of new anti-viral therapeutics.
History
Deposition
May 31, 2021
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Header (metadata) release
Jun 9, 2021
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Map release
Jun 9, 2021
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Update
May 29, 2024
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Current status
May 29, 2024
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
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