7B3C

Structure of elongating SARS-CoV-2 RNA-dependent RNA polymerase with Remdesivir at position -4 (structure 2)

7B3C の概要

• エントリーDOI: 10.2210/pdb7b3c/pdb
• EMDBエントリー: 11993 11994 11995
• 分子名称: RNA-directed RNA polymerase nsp12, Non-structural protein 8, Non-structural protein 7, ... (6 entities in total)
• 機能のキーワード: sars-cov-2, polymerase, transcription, replication, rna, remdesivir, inhibition, nucleotide analogue, viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2; 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 161851.01

構造登録者

Kokic, G.,Hillen, H.S.,Tegunov, D.,Dienemann, C.,Seitz, F.,Schmitzova, J.,Farnung, L.,Siewert, A.,Hoebartner, C.,Cramer, P. (登録日: 2020-11-30, 公開日: 2020-12-23, 最終更新日: 2024-07-10)

主引用文献

Kokic, G.,Hillen, H.S.,Tegunov, D.,Dienemann, C.,Seitz, F.,Schmitzova, J.,Farnung, L.,Siewert, A.,Hobartner, C.,Cramer, P.
Mechanism of SARS-CoV-2 polymerase stalling by remdesivir.
Nat Commun, 12:279-279, 2021

PubMed Abstract: 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.

PubMed: 33436624
DOI: 10.1038/s41467-020-20542-0

実験手法

ELECTRON MICROSCOPY (3.4 Å)