tetano
Editor, Senior Moderator
Nat Commun
. 2020 Jul 24;11(1):3718.
doi: 10.1038/s41467-020-17496-8.
Structural basis of RNA cap modification by SARS-CoV-2
Thiruselvam Viswanathan[SUP] 1 2 [/SUP], Shailee Arya[SUP] 1 2 [/SUP], Siu-Hong Chan[SUP] 3 [/SUP], Shan Qi[SUP] 1 2 [/SUP], Nan Dai[SUP] 3 [/SUP], Anurag Misra[SUP] 1 2 [/SUP], Jun-Gyu Park[SUP] 4 [/SUP], Fatai Oladunni[SUP] 4 [/SUP], Dmytro Kovalskyy[SUP] 1 [/SUP], Robert A Hromas[SUP] 5 [/SUP], Luis Martinez-Sobrido[SUP] 4 [/SUP], Yogesh K Gupta[SUP] 6 7 [/SUP]
Affiliations
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 ?) ligand-binding site unique to SARS-CoV-2, which can alternatively be targeted, in addition to RNA cap and SAM pockets, for antiviral development.
. 2020 Jul 24;11(1):3718.
doi: 10.1038/s41467-020-17496-8.
Structural basis of RNA cap modification by SARS-CoV-2
Thiruselvam Viswanathan[SUP] 1 2 [/SUP], Shailee Arya[SUP] 1 2 [/SUP], Siu-Hong Chan[SUP] 3 [/SUP], Shan Qi[SUP] 1 2 [/SUP], Nan Dai[SUP] 3 [/SUP], Anurag Misra[SUP] 1 2 [/SUP], Jun-Gyu Park[SUP] 4 [/SUP], Fatai Oladunni[SUP] 4 [/SUP], Dmytro Kovalskyy[SUP] 1 [/SUP], Robert A Hromas[SUP] 5 [/SUP], Luis Martinez-Sobrido[SUP] 4 [/SUP], Yogesh K Gupta[SUP] 6 7 [/SUP]
Affiliations
- PMID: 32709886
- DOI: 10.1038/s41467-020-17496-8
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 ?) ligand-binding site unique to SARS-CoV-2, which can alternatively be targeted, in addition to RNA cap and SAM pockets, for antiviral development.