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TitleMechanism of SARS-CoV-2 polymerase stalling by remdesivir.
Journal, issue, pagesNat Commun, Vol. 12, Issue 1, Page 279, Year 2021
Publish dateJan 12, 2021
AuthorsGoran Kokic / Hauke S Hillen / Dimitry Tegunov / Christian Dienemann / Florian Seitz / Jana Schmitzova / Lucas Farnung / Aaron Siewert / Claudia Höbartner / Patrick Cramer /
PubMed AbstractRemdesivir is the only FDA-approved drug for the treatment of COVID-19 patients. The active form of remdesivir acts as a nucleoside analog and inhibits the RNA-dependent RNA polymerase (RdRp) of ...Remdesivir is the only FDA-approved drug for the treatment of COVID-19 patients. The active form of remdesivir acts as a nucleoside analog and inhibits the RNA-dependent RNA polymerase (RdRp) of coronaviruses including SARS-CoV-2. Remdesivir is incorporated by the RdRp into the growing RNA product and allows for addition of three more nucleotides before RNA synthesis stalls. Here we use synthetic RNA chemistry, biochemistry and cryo-electron microscopy to establish the molecular mechanism of remdesivir-induced RdRp stalling. We show that addition of the fourth nucleotide following remdesivir incorporation into the RNA product is impaired by a barrier to further RNA translocation. This translocation barrier causes retention of the RNA 3'-nucleotide in the substrate-binding site of the RdRp and interferes with entry of the next nucleoside triphosphate, thereby stalling RdRp. In the structure of the remdesivir-stalled state, the 3'-nucleotide of the RNA product is matched and located with the template base in the active center, and this may impair proofreading by the viral 3'-exonuclease. These mechanistic insights should facilitate the quest for improved antivirals that target coronavirus replication.
External linksNat Commun / PubMed:33436624 / PubMed Central
MethodsEM (single particle)
Resolution2.8 - 3.4 Å
Structure data

EMDB-11993, PDB-7b3b:
Structure of elongating SARS-CoV-2 RNA-dependent RNA polymerase with Remdesivir at position -3 (structure 1)
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-11994, PDB-7b3c:
Structure of elongating SARS-CoV-2 RNA-dependent RNA polymerase with Remdesivir at position -4 (structure 2)
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-11995, PDB-7b3d:
Structure of elongating SARS-CoV-2 RNA-dependent RNA polymerase with AMP at position -4 (structure 3)
Method: EM (single particle) / Resolution: 2.8 Å

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • severe acute respiratory syndrome coronavirus 2
KeywordsVIRAL PROTEIN / SARS-CoV-2 / Polymerase / Transcription / Replication / RNA / Remdesivir / Inhibition / Nucleotide Analogue

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