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SARS-CoV-2 Nsp16 activation mechanism and a cryptic pocket with pan-coronavirus antiviral potential

Neha Vithani, Michael D. Ward, Maxwell I. Zimmerman, Borna Novak, Jonathan H. Borowsky, View ORCID ProfileSukrit Singh, Gregory R. Bowman
doi: https://doi.org/10.1101/2020.12.10.420109
Neha Vithani
1Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States
2Center for Science and Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, Missouri 63130, United States
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Michael D. Ward
1Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States
2Center for Science and Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, Missouri 63130, United States
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Maxwell I. Zimmerman
1Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States
2Center for Science and Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, Missouri 63130, United States
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Borna Novak
1Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States
2Center for Science and Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, Missouri 63130, United States
3Medical Scientist Training Program, Washington University in St. Louis School of Medicine, St. Louis, Missouri 63110, United States
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Jonathan H. Borowsky
1Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States
2Center for Science and Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, Missouri 63130, United States
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Sukrit Singh
1Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States
2Center for Science and Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, Missouri 63130, United States
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  • ORCID record for Sukrit Singh
Gregory R. Bowman
1Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States
2Center for Science and Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, Missouri 63130, United States
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  • For correspondence: g.bowman@wustl.edu
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Abstract

Coronaviruses have caused multiple epidemics in the past two decades, in addition to the current COVID-19 pandemic that is severely damaging global health and the economy. Coronaviruses employ between twenty and thirty proteins to carry out their viral replication cycle including infection, immune evasion, and replication. Among these, nonstructural protein 16 (Nsp16), a 2’-O-methyltransferase, plays an essential role in immune evasion. Nsp16 achieves this by mimicking its human homolog, CMTr1, which methylates mRNA to enhance translation efficiency and distinguish self from other. Unlike human CMTr1, Nsp16 requires a binding partner, Nsp10, to activate its enzymatic activity. The requirement of this binding partner presents two questions that we investigate in this manuscript. First, how does Nsp10 activate Nsp16? While experimentally-derived structures of the active Nsp16/Nsp10 complex exist, structures of inactive, monomeric Nsp16 have yet to be solved. Therefore, it is unclear how Nsp10 activates Nsp16. Using over one millisecond of molecular dynamics simulations of both Nsp16 and its complex with Nsp10, we investigate how the presence of Nsp10 shifts Nsp16’s conformational ensemble in order to activate it. Second, guided by this activation mechanism and Markov state models (MSMs), we investigate if Nsp16 adopts inactive structures with cryptic pockets that, if targeted with a small molecule, could inhibit Nsp16 by stabilizing its inactive state. After identifying such a pocket in SARS-CoV-2 Nsp16, we show that this cryptic pocket also opens in SARS-CoV-1 and MERS, but not in human CMTr1. Therefore, it may be possible to develop pan-coronavirus antivirals that target this cryptic pocket.

Statement of Significance Coronaviruses are a major threat to human health. These viruses employ molecular machines, called proteins, to infect host cells and replicate. Characterizing the structure and dynamics of these proteins could provide a basis for designing small molecule antivirals. In this work, we use computer simulations to understand the moving parts of an essential SARS-CoV-2 protein, understand how a binding partner turns it on and off, and identify a novel pocket that antivirals could target to shut this protein off. The pocket is also present in other coronaviruses but not in the related human protein, so it could be a valuable target for pan-coronavirus antivirals.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 10, 2020.
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SARS-CoV-2 Nsp16 activation mechanism and a cryptic pocket with pan-coronavirus antiviral potential
Neha Vithani, Michael D. Ward, Maxwell I. Zimmerman, Borna Novak, Jonathan H. Borowsky, Sukrit Singh, Gregory R. Bowman
bioRxiv 2020.12.10.420109; doi: https://doi.org/10.1101/2020.12.10.420109
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SARS-CoV-2 Nsp16 activation mechanism and a cryptic pocket with pan-coronavirus antiviral potential
Neha Vithani, Michael D. Ward, Maxwell I. Zimmerman, Borna Novak, Jonathan H. Borowsky, Sukrit Singh, Gregory R. Bowman
bioRxiv 2020.12.10.420109; doi: https://doi.org/10.1101/2020.12.10.420109

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