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 and Yogesh K. Gupta ()
Additional contact information
Thiruselvam Viswanathan: Greehey Children’s Cancer Research Institute, University of Texas Health at San Antonio
Shailee Arya: Greehey Children’s Cancer Research Institute, University of Texas Health at San Antonio
Siu-Hong Chan: New England Biolabs
Shan Qi: Greehey Children’s Cancer Research Institute, University of Texas Health at San Antonio
Nan Dai: New England Biolabs
Anurag Misra: Greehey Children’s Cancer Research Institute, University of Texas Health at San Antonio
Jun-Gyu Park: Texas Biomedical Research Institute
Fatai Oladunni: Texas Biomedical Research Institute
Dmytro Kovalskyy: Greehey Children’s Cancer Research Institute, University of Texas Health at San Antonio
Robert A. Hromas: University of Texas Health at San Antonio
Luis Martinez-Sobrido: Texas Biomedical Research Institute
Yogesh K. Gupta: Greehey Children’s Cancer Research Institute, University of Texas Health at San Antonio

Nature Communications, 2020, vol. 11, issue 1, 1-7

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17496-8

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