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Structure paper

TitleStructural basis for substrate selection by the SARS-CoV-2 replicase.
Journal, issue, pagesNature, Vol. 614, Issue 7949, Page 781-787, Year 2023
Publish dateFeb 1, 2023
AuthorsBrandon F Malone / Jason K Perry / Paul Dominic B Olinares / Hery W Lee / James Chen / Todd C Appleby / Joy Y Feng / John P Bilello / Honkit Ng / Johanna Sotiris / Mark Ebrahim / Eugene Y D Chua / Joshua H Mendez / Ed T Eng / Robert Landick / Matthias Götte / Brian T Chait / Elizabeth A Campbell / Seth A Darst /
PubMed AbstractThe SARS-CoV-2 RNA-dependent RNA polymerase coordinates viral RNA synthesis as part of an assembly known as the replication-transcription complex (RTC). Accordingly, the RTC is a target for ...The SARS-CoV-2 RNA-dependent RNA polymerase coordinates viral RNA synthesis as part of an assembly known as the replication-transcription complex (RTC). Accordingly, the RTC is a target for clinically approved antiviral nucleoside analogues, including remdesivir. Faithful synthesis of viral RNAs by the RTC requires recognition of the correct nucleotide triphosphate (NTP) for incorporation into the nascent RNA. To be effective inhibitors, antiviral nucleoside analogues must compete with the natural NTPs for incorporation. How the SARS-CoV-2 RTC discriminates between the natural NTPs, and how antiviral nucleoside analogues compete, has not been discerned in detail. Here, we use cryogenic-electron microscopy to visualize the RTC bound to each of the natural NTPs in states poised for incorporation. Furthermore, we investigate the RTC with the active metabolite of remdesivir, remdesivir triphosphate (RDV-TP), highlighting the structural basis for the selective incorporation of RDV-TP over its natural counterpart adenosine triphosphate. Our results explain the suite of interactions required for NTP recognition, informing the rational design of antivirals. Our analysis also yields insights into nucleotide recognition by the nsp12 NiRAN (nidovirus RdRp-associated nucleotidyltransferase), an enigmatic catalytic domain essential for viral propagation. The NiRAN selectively binds guanosine triphosphate, strengthening proposals for the role of this domain in the formation of the 5' RNA cap.
External linksNature / PubMed:36725929 / PubMed Central
MethodsEM (single particle)
Resolution2.67 - 3.38 Å
Structure data

26639

7uo4

EMDB-26639, PDB-7uo4:
SARS-CoV-2 replication-transcription complex bound to Remdesivir triphosphate, in a pre-catalytic state
Method: EM (single particle) / Resolution: 3.38 Å

26641

7uo7

EMDB-26641, PDB-7uo7:
SARS-CoV-2 replication-transcription complex bound to ATP, in a pre-catalytic state
Method: EM (single particle) / Resolution: 3.09 Å

26642

7uo9

EMDB-26642, PDB-7uo9:
SARS-CoV-2 replication-transcription complex bound to UTP, in a pre-catalytic state
Method: EM (single particle) / Resolution: 3.13 Å

26645

7uob

EMDB-26645, PDB-7uob:
SARS-CoV-2 replication-transcription complex bound to GTP, in a pre-catalytic state
Method: EM (single particle) / Resolution: 2.68 Å

26646

7uoe

EMDB-26646, PDB-7uoe:
SARS-CoV-2 replication-transcription complex bound to CTP, in a pre-catalytic state
Method: EM (single particle) / Resolution: 2.67 Å

Chemicals

ChemComp-NWX:
[[(2~{R},3~{S},4~{R},5~{R})-5-(4-azanylpyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] phosphono hydrogen phosphate

ChemComp-MG:
Unknown entry

ChemComp-ZN:
Unknown entry

ChemComp-HOH:
WATER / Water

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM / Adenosine triphosphate

ChemComp-UTP:
URIDINE 5'-TRIPHOSPHATE / UTP*YM / Uridine triphosphate

ChemComp-GTP:
GUANOSINE-5'-TRIPHOSPHATE / GTP, energy-carrying molecule*YM / Guanosine triphosphate

ChemComp-L2B:
3'-DEOXYURIDINE-5'-MONOPHOSPHATE / Deoxyuridine monophosphate

ChemComp-CTP:
CYTIDINE-5'-TRIPHOSPHATE / Cytidine triphosphate

Source
  • severe acute respiratory syndrome coronavirus 2
  • synthetic construct (others)
KeywordsREPLICATION / RNA-directed 5'-3' RNA polymerase activity / positive stranded viral RNA replication

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