Journal: Proc Natl Acad Sci U S A / Year: 2021 Title: Structure of the SARS-CoV-2 RNA-dependent RNA polymerase in the presence of favipiravir-RTP. Authors: Katerina Naydenova / Kyle W Muir / Long-Fei Wu / Ziguo Zhang / Francesca Coscia / Mathew J Peet / Pablo Castro-Hartmann / Pu Qian / Kasim Sader / Kyle Dent / Dari Kimanius / John D ...Authors: Katerina Naydenova / Kyle W Muir / Long-Fei Wu / Ziguo Zhang / Francesca Coscia / Mathew J Peet / Pablo Castro-Hartmann / Pu Qian / Kasim Sader / Kyle Dent / Dari Kimanius / John D Sutherland / Jan Löwe / David Barford / Christopher J Russo / Abstract: The RNA polymerase inhibitor favipiravir is currently in clinical trials as a treatment for infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), despite limited information ...The RNA polymerase inhibitor favipiravir is currently in clinical trials as a treatment for infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), despite limited information about the molecular basis for its activity. Here we report the structure of favipiravir ribonucleoside triphosphate (favipiravir-RTP) in complex with the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) bound to a template:primer RNA duplex, determined by electron cryomicroscopy (cryoEM) to a resolution of 2.5 Å. The structure shows clear evidence for the inhibitor at the catalytic site of the enzyme, and resolves the conformation of key side chains and ions surrounding the binding pocket. Polymerase activity assays indicate that the inhibitor is weakly incorporated into the RNA primer strand, and suppresses RNA replication in the presence of natural nucleotides. The structure reveals an unusual, nonproductive binding mode of favipiravir-RTP at the catalytic site of SARS-CoV-2 RdRp, which explains its low rate of incorporation into the RNA primer strand. Together, these findings inform current and future efforts to develop polymerase inhibitors for SARS coronaviruses.
History
Deposition
Sep 4, 2020
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Header (metadata) release
Sep 23, 2020
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Map release
Sep 23, 2020
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Update
Jul 10, 2024
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Current status
Jul 10, 2024
Processing site: PDBe / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
EMPIAR-10517 (Title: Movies of Nsp7-Nsp8-Nsp12 SARS-CoV2 RNA-dependent RNA polymerase in complex with template:primer dsRNA and favipiravir-RTP Data size: 46.9 TB Data #1: Unaligned multi-frame micrographs of SARS-CoV-2 RNA-dependent RNA polymerase in compex with template:primer dsRNA and favipiravir-RTP [micrographs - multiframe])
Film or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 24.72 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron optics
Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
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Image processing
Startup model
Type of model: EMDB MAP Details: The structure was determined by molecular replacement using 7BV2. Thereafter, the model was manually corrected in Coot and refined in Phenix, using real-space refinement.
Final reconstruction
Resolution.type: BY AUTHOR / Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 40828
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