Structural basis of RNA cap modification by SARS-CoV-2

Thiruselvam Viswanathan, Shailee Arya, Siu Hong Chan, Shan Qi, Nan Dai, Anurag Misra, Jun Gyu Park, Fatai Oladunni, Dmytro Kovalskyy, Robert A. Hromas, Luis Martinez-Sobrido, Yogesh K. Gupta

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19 illness, has caused millions of infections worldwide. In SARS coronaviruses, the non-structural protein 16 (nsp16), in conjunction with nsp10, methylates the 5′-end of virally encoded mRNAs to mimic cellular mRNAs, thus protecting the virus from host innate immune restriction. We report here the high-resolution structure of a ternary complex of SARS-CoV-2 nsp16 and nsp10 in the presence of cognate RNA substrate analogue and methyl donor, S-adenosyl methionine (SAM). The nsp16/nsp10 heterodimer is captured in the act of 2′-O methylation of the ribose sugar of the first nucleotide of SARS-CoV-2 mRNA. We observe large conformational changes associated with substrate binding as the enzyme transitions from a binary to a ternary state. This induced fit model provides mechanistic insights into the 2′-O methylation of the viral mRNA cap. We also discover a distant (25 Å) ligand-binding site unique to SARS-CoV-2, which can alternatively be targeted, in addition to RNA cap and SAM pockets, for antiviral development.

Original languageEnglish (US)
Article number3718
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Viswanathan, T., Arya, S., Chan, S. H., Qi, S., Dai, N., Misra, A., Park, J. G., Oladunni, F., Kovalskyy, D., Hromas, R. A., Martinez-Sobrido, L., & Gupta, Y. K. (2020). Structural basis of RNA cap modification by SARS-CoV-2. Nature communications, 11(1), [3718]. https://doi.org/10.1038/s41467-020-17496-8