8GWG

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

Summary for 8GWG

• Entry DOI: 10.2210/pdb8gwg/pdb
• EMDB information: 34312
• Descriptor: RNA-directed RNA polymerase, Non-structural protein 8, Non-structural protein 7, ... (10 entities in total)
• Functional Keywords: sars-cov-2, capping, nucleotide analogue inhibitor, cryo-em, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2; More
• Total number of polymer chains: 9
• Total formula weight: 326154.16

Authors

Yan, L.M.,Huang, Y.C.,Ge, J.,Liu, Z.Y.,Gao, Y.,Rao, Z.H.,Lou, Z.Y. (deposition date: 2022-09-17, release date: 2022-12-14, Last modification date: 2024-07-03)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (3.37 Å)