8GWO

A mechanism for SARS-CoV-2 RNA capping and its inhibition by nucleotide analogue inhibitors

8GWO の概要

• エントリーDOI: 10.2210/pdb8gwo/pdb
• EMDBエントリー: 34318
• 分子名称: RNA-directed RNA polymerase, URIDINE-5'-MONOPHOSPHATE, Non-structural protein 8, ... (10 entities in total)
• 機能のキーワード: sars-cov-2, capping, nucleotide analogue inhibitor, cryo-em, 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: 9
• 化学式量合計: 326073.90

構造登録者

Yan, L.M.,Huang, Y.C.,Ge, J.,Liu, Z.Y.,Gao, Y.,Rao, Z.H.,Lou, Z.Y. (登録日: 2022-09-17, 公開日: 2022-11-30, 最終更新日: 2024-10-30)

主引用文献

Yan, L.,Huang, Y.,Ge, J.,Liu, Z.,Lu, P.,Huang, B.,Gao, S.,Wang, J.,Tan, L.,Ye, S.,Yu, F.,Lan, W.,Xu, S.,Zhou, F.,Shi, L.,Guddat, L.W.,Gao, Y.,Rao, Z.,Lou, Z.
A mechanism for SARS-CoV-2 RNA capping and its inhibition by nucleotide analog inhibitors.
Cell, 185:4347-4360.e17, 2022

PubMed Abstract: Decoration of cap on viral RNA plays essential roles in SARS-CoV-2 proliferation. Here, we report a mechanism for SARS-CoV-2 RNA capping and document structural details at atomic resolution. The NiRAN domain in polymerase catalyzes the covalent link of RNA 5' end to the first residue of nsp9 (termed as RNAylation), thus being an intermediate to form cap core (GpppA) with GTP catalyzed again by NiRAN. We also reveal that triphosphorylated nucleotide analog inhibitors can be bonded to nsp9 and fit into a previously unknown "Nuc-pocket" in NiRAN, thus inhibiting nsp9 RNAylation and formation of GpppA. S-loop (residues 50-KTN-52) in NiRAN presents a remarkable conformational shift observed in RTC bound with sofosbuvir monophosphate, reasoning an "induce-and-lock" mechanism to design inhibitors. These findings not only improve the understanding of SARS-CoV-2 RNA capping and the mode of action of NAIs but also provide a strategy to design antiviral drugs.

PubMed: 36335936
DOI: 10.1016/j.cell.2022.09.037

実験手法

ELECTRON MICROSCOPY (3.8 Å)