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Title: High-resolution structures of the SARS-CoV-2 2′- O -methyltransferase reveal strategies for structure-based inhibitor design

Abstract

There are currently no antiviral therapies specific for SARS-CoV-2, the virus responsible for the global pandemic disease COVID-19. To facilitate structure-based drug design, we conducted an x-ray crystallographic study of the SARS-CoV-2 nsp16-nsp10 2′- O -methyltransferase complex, which methylates Cap-0 viral mRNAs to improve viral protein translation and to avoid host immune detection. We determined the structures for nsp16-nsp10 heterodimers bound to the methyl donor S -adenosylmethionine (SAM), the reaction product S -adenosylhomocysteine (SAH), or the SAH analog sinefungin (SFG). We also solved structures for nsp16-nsp10 in complex with the methylated Cap-0 analog m 7 GpppA and either SAM or SAH. Comparative analyses between these structures and published structures for nsp16 from other betacoronaviruses revealed flexible loops in open and closed conformations at the m 7 GpppA-binding pocket. Bound sulfates in several of the structures suggested the location of the ribonucleic acid backbone phosphates in the ribonucleotide-binding groove. Additional nucleotide-binding sites were found on the face of the protein opposite the active site. These various sites and the conserved dimer interface could be exploited for the development of antiviral inhibitors.

Authors:
ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [2]; ORCiD logo [1]
  1. Department of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA., Center for Structural Genomics of Infectious Diseases, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
  2. Northwestern Synchrotron Research Center, Life Sciences Collaborative Access Team, Northwestern University, Argonne, IL 60439, USA.
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1668455
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Published Article
Journal Name:
Science Signaling
Additional Journal Information:
Journal Name: Science Signaling Journal Volume: 13 Journal Issue: 651; Journal ID: ISSN 1945-0877
Publisher:
American Association for the Advancement of Science (AAAS)
Country of Publication:
United States
Language:
English

Citation Formats

Rosas-Lemus, Monica, Minasov, George, Shuvalova, Ludmilla, Inniss, Nicole L., Kiryukhina, Olga, Brunzelle, Joseph, and Satchell, Karla J. F. High-resolution structures of the SARS-CoV-2 2′- O -methyltransferase reveal strategies for structure-based inhibitor design. United States: N. p., 2020. Web. https://doi.org/10.1126/scisignal.abe1202.
Rosas-Lemus, Monica, Minasov, George, Shuvalova, Ludmilla, Inniss, Nicole L., Kiryukhina, Olga, Brunzelle, Joseph, & Satchell, Karla J. F. High-resolution structures of the SARS-CoV-2 2′- O -methyltransferase reveal strategies for structure-based inhibitor design. United States. https://doi.org/10.1126/scisignal.abe1202
Rosas-Lemus, Monica, Minasov, George, Shuvalova, Ludmilla, Inniss, Nicole L., Kiryukhina, Olga, Brunzelle, Joseph, and Satchell, Karla J. F. Tue . "High-resolution structures of the SARS-CoV-2 2′- O -methyltransferase reveal strategies for structure-based inhibitor design". United States. https://doi.org/10.1126/scisignal.abe1202.
@article{osti_1668455,
title = {High-resolution structures of the SARS-CoV-2 2′- O -methyltransferase reveal strategies for structure-based inhibitor design},
author = {Rosas-Lemus, Monica and Minasov, George and Shuvalova, Ludmilla and Inniss, Nicole L. and Kiryukhina, Olga and Brunzelle, Joseph and Satchell, Karla J. F.},
abstractNote = {There are currently no antiviral therapies specific for SARS-CoV-2, the virus responsible for the global pandemic disease COVID-19. To facilitate structure-based drug design, we conducted an x-ray crystallographic study of the SARS-CoV-2 nsp16-nsp10 2′- O -methyltransferase complex, which methylates Cap-0 viral mRNAs to improve viral protein translation and to avoid host immune detection. We determined the structures for nsp16-nsp10 heterodimers bound to the methyl donor S -adenosylmethionine (SAM), the reaction product S -adenosylhomocysteine (SAH), or the SAH analog sinefungin (SFG). We also solved structures for nsp16-nsp10 in complex with the methylated Cap-0 analog m 7 GpppA and either SAM or SAH. Comparative analyses between these structures and published structures for nsp16 from other betacoronaviruses revealed flexible loops in open and closed conformations at the m 7 GpppA-binding pocket. Bound sulfates in several of the structures suggested the location of the ribonucleic acid backbone phosphates in the ribonucleotide-binding groove. Additional nucleotide-binding sites were found on the face of the protein opposite the active site. These various sites and the conserved dimer interface could be exploited for the development of antiviral inhibitors.},
doi = {10.1126/scisignal.abe1202},
journal = {Science Signaling},
number = 651,
volume = 13,
place = {United States},
year = {2020},
month = {9}
}

Journal Article:
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Publisher's Version of Record
https://doi.org/10.1126/scisignal.abe1202

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