The mechanism of RNA capping by SARS-CoV-2.
Nature
; 609(7928): 793-800, 2022 09.
Article
in English
| MEDLINE | ID: covidwho-1984402
ABSTRACT
The RNA genome of SARS-CoV-2 contains a 5' cap that facilitates the translation of viral proteins, protection from exonucleases and evasion of the host immune response1-4. How this cap is made in SARS-CoV-2 is not completely understood. Here we reconstitute the N7- and 2'-O-methylated SARS-CoV-2 RNA cap (7MeGpppA2'-O-Me) using virally encoded non-structural proteins (nsps). We show that the kinase-like nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain5 of nsp12 transfers the RNA to the amino terminus of nsp9, forming a covalent RNA-protein intermediate (a process termed RNAylation). Subsequently, the NiRAN domain transfers the RNA to GDP, forming the core cap structure GpppA-RNA. The nsp146 and nsp167 methyltransferases then add methyl groups to form functional cap structures. Structural analyses of the replication-transcription complex bound to nsp9 identified key interactions that mediate the capping reaction. Furthermore, we demonstrate in a reverse genetics system8 that the N terminus of nsp9 and the kinase-like active-site residues in the NiRAN domain are required for successful SARS-CoV-2 replication. Collectively, our results reveal an unconventional mechanism by which SARS-CoV-2 caps its RNA genome, thus exposing a new target in the development of antivirals to treat COVID-19.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Viral Proteins
/
RNA Caps
/
RNA, Viral
/
SARS-CoV-2
Type of study:
Experimental Studies
/
Randomized controlled trials
Limits:
Humans
Language:
English
Journal:
Nature
Year:
2022
Document Type:
Article
Affiliation country:
S41586-022-05185-z
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