7AAP

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

7AAP の概要

• エントリーDOI: 10.2210/pdb7aap/pdb
• EMDBエントリー: 11692
• 分子名称: Non-structural protein 12, Non-structural protein 8, Non-structural protein 7, ... (9 entities in total)
• 機能のキーワード: rna-dependent rna polymerase, favipiravir, sars-cov2, ncovid19, viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 181600.83

構造登録者

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. (登録日: 2020-09-04, 公開日: 2020-09-23, 最終更新日: 2024-07-10)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (2.5 Å)