7AAP

Nsp7-Nsp8-Nsp12 SARS-CoV2 RNA-dependent RNA polymerase in complex with template:primer dsRNA and favipiravir-RTP

Summary for 7AAP

• Entry DOI: 10.2210/pdb7aap/pdb
• EMDB information: 11692
• Descriptor: Non-structural protein 12, Non-structural protein 8, Non-structural protein 7, ... (9 entities in total)
• Functional Keywords: rna-dependent rna polymerase, favipiravir, sars-cov2, ncovid19, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV); More
• Total number of polymer chains: 6
• Total formula weight: 181600.83

Authors

Naydenova, K.,Muir, K.W.,Wu, L.F.,Zhang, Z.,Coscia, F.,Peet, M.,Castro-Hartman, P.,Qian, P.,Sader, K.,Dent, K.,Kimanius, D.,Sutherland, J.D.,Lowe, J.,Barford, D.,Russo, C.J. (deposition date: 2020-09-04, release date: 2020-09-23, Last modification date: 2024-07-10)

Primary citation

Naydenova, K.,Muir, K.W.,Wu, L.F.,Zhang, Z.,Coscia, F.,Peet, M.J.,Castro-Hartmann, P.,Qian, P.,Sader, K.,Dent, K.,Kimanius, D.,Sutherland, J.D.,Lowe, J.,Barford, D.,Russo, C.J.
Structure of the SARS-CoV-2 RNA-dependent RNA polymerase in the presence of favipiravir-RTP.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed 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 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.

PubMed: 33526596
DOI: 10.1073/pnas.2021946118

Experimental method

ELECTRON MICROSCOPY (2.5 Å)