期刊
NATURE
卷 609, 期 7928, 页码 793-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41586-022-05185-z
关键词
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资金
- Cancer Prevention & Research Institute of Texas (CPRIT) [RP170644]
- W. M. Keck Foundation Medical Research Grant
- National Institutes of Health [R01GM135189, 1DP1AI158124]
- Welch Foundation [I-1911]
- Life Sciences Research Foundation Fellowship
- Polish National Agency for Scientific Exchange scholarship [PPN/BEK/2018/1/00431]
- NIH [R24GM141526]
- CPRIT [RR150033]
In this study, we reconstituted the formation mechanism of the SARS-CoV-2 RNA cap and identified key domains and interactions involved. This finding reveals a new target for the treatment of COVID-19.
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 response(1-4). 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 ((7Me)GpppA(2'- O-Me)) using virally encoded non-structural proteins (nsps). We show that the kinase-like nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain(5) 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 nsp14(6) and nsp16(7) 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 system(8) 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.
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