A Mechanism for SARS-CoV-2 RNA Capping and Its Inhibition by Nucleotide Analog Inhibitors

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2022 Nov 6

PMID 36335936

Authors

Liming Yan

Yucen Huang

Ji Ge

Zhenyu Liu

Pengchi Lu

Bo Huang

Shan Gao

Junbo Wang

Liping Tan

Sihan Ye

Fengxi Yu

Weiqi Lan

Shiya Xu

Feng Zhou

Lei Shi

Luke W Guddat

Yan Gao

Zihe Rao

Zhiyong Lou

Affiliations

Soon will be listed here.

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.

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