RT Journal Article
SR Electronic
T1 Structural Basis of RNA Cap Modification by SARS-CoV-2 Coronavirus
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.26.061705
DO 10.1101/2020.04.26.061705
A1 Thiruselvam Viswanathan
A1 Shailee Arya
A1 Siu-Hong Chan
A1 Shan Qi
A1 Nan Dai
A1 Robert A. Hromas
A1 Jun-Gyu Park
A1 Fatai Oladunni
A1 Luis Martinez-Sobrido
A1 Yogesh K. Gupta
YR 2020
UL http://biorxiv.org/content/early/2020/04/26/2020.04.26.061705.abstract
AB The novel severe acute respiratory syndrome coronoavirus-2 (SARS-CoV-2), the causative agent of COVID-19 illness, has caused over 2 million infections worldwide in four months. In SARS coronaviruses, the non-structural protein 16 (nsp16) 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 full-length nsp16 and nsp10 of SARS-CoV-2 in the presence of cognate RNA substrate and a methyl donor, S-adenosyl methionine. The nsp16/nsp10 heterodimer was captured in the act of 2’-O methylation of the ribose sugar of the first nucleotide of SARS-CoV-2 mRNA. We reveal large conformational changes associated with substrate binding as the enzyme transitions from a binary to a ternary state. This structure provides new mechanistic insights into the 2’-O methylation of the viral mRNA cap. We also discovered a distantly located ligand-binding site unique to SARS-CoV-2 that may serve as an alternative target site for antiviral development.Competing Interest Statement1. Yogesh K. Gupta is founder of Atomic Therapeutics. This affiliation does not affect the authors impartiality, adherence to journal standards and policies, or availability of data. 2. Robert A. Hromas owns equity in Dialectic Therapeutics and Abfero. This affiliation does not affect the authors impartiality, adherence to journal standards and policies, or availability of data. 3. Siu-Hong Chan and Nan Dai are employees of New England Biolabs, a manufacturer and vendor of molecular biology reagents, including vaccinia RNA capping enzyme and cap 2O methyltransferase. This affiliation does not affect the authors impartiality, adherence to journal standards and policies, or availability of data.