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TitleStructural basis for selective remdesivir incorporation by SARS-CoV-2 RNA polymerase, and S759A resistance.
Journal, issue, pagesbioRxiv, Year 2025
Publish dateSep 4, 2025
AuthorsCalvin J Gordon / Mizar F Oliva / Hery W Lee / Quinten Goovaerts / Brent De Wijngaert / Matthias Götte / Kalyan Das
PubMed AbstractNucleoside analogs (NAs) have been successfully used to treat viral infections. dNTP analogs are primarily DNA chain terminators, while NTP analogs, such as remdesivir, can inhibit as delayed chain ...Nucleoside analogs (NAs) have been successfully used to treat viral infections. dNTP analogs are primarily DNA chain terminators, while NTP analogs, such as remdesivir, can inhibit as delayed chain terminators or when in the template strand. Determining the frequency of remdesivir triphosphate (RTP) incorporation in the presence of the competing ATP can help in understanding different modes of viral RNA-dependent RNA polymerase (RdRp) inhibition by NTP analogs. We employed enzymatic assays, mass spectrometry, and cryo-EM to show that SARS-CoV-2 RdRp preferentially incorporates RTP, outcompeting 10-fold higher ATP concentration; however, successive RTP incorporations are less favoured when ATP is present. Structures of SARS-CoV-2 RdRp in this and previous studies demonstrate resilience of remdesivir:UMP base pair to translocation, explaining the reduced preference for conjugate incorporations. Together, the RTP versus ATP incorporation is driven by their relative concentration and structural rigidity of remdesivir:UMP, ultimately limiting the number of incorporated remdesivir in a fully synthesized RNA strand. The S759A mutant confers RTP resistance, and the structures of S759A RdRp catalytic complexes reveal that altered ribose-ring conformation and repositioning of the primer 3'-end nucleotide contribute to RTP resistance. These findings enhance our understanding of non-obligate NTP analogs and provide insight into S759A resistance mechanism.
External linksbioRxiv / PubMed:40950230 / PubMed Central
MethodsEM (single particle)
Resolution2.8 - 3.1 Å
Structure data

54692

9sao

EMDB-54692, PDB-9sao:
Cryo-EM structure of SARS CoV-2 RdRp S759A mutant in complex with 20-40mer RNA incorporating remdesivir
Method: EM (single particle) / Resolution: 2.9 Å

54693

9sap

EMDB-54693, PDB-9sap:
Cryo-EM structure of SARS CoV-2 RdRp wild-type in complex with 20-40mer RNA incorporating Remdesivir
Method: EM (single particle) / Resolution: 2.9 Å

54694

9saq

EMDB-54694, PDB-9saq:
Cryo-EM structure of SARS CoV-2 RdRp S759A mutant in complex with 20-40mer RNA incorporating ATP
Method: EM (single particle) / Resolution: 3.1 Å

54695

9sar

EMDB-54695, PDB-9sar:
Cryo-EM structure of SARS CoV-2 RdRp wild-type in complex with 20-40mer RNA incorporating ATP
Method: EM (single particle) / Resolution: 2.8 Å

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • severe acute respiratory syndrome coronavirus 2
KeywordsVIRAL PROTEIN / RNA-dependent RNA polymerase / SARS CoV-2 / transcription / ATP / remdesivir / S759A mutant

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