Author
Listed:
- Thiruselvam Viswanathan
(Greehey Children’s Cancer Research Institute, University of Texas Health at San Antonio
University of Texas Health at San Antonio)
- Shailee Arya
(Greehey Children’s Cancer Research Institute, University of Texas Health at San Antonio
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
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
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
University of Texas Health at San Antonio)
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.
Suggested Citation
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. Gupt, 2020.
"Structural basis of RNA cap modification by SARS-CoV-2,"
Nature Communications, Nature, vol. 11(1), pages 1-7, December.
Handle:
RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17496-8
DOI: 10.1038/s41467-020-17496-8
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