2. Academic Validation
  3. A mechanism for SARS-CoV-2 RNA capping and its inhibition by nucleotide analog inhibitors

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

  • Cell. 2022 Nov 10;185(23):4347-4360.e17. doi: 10.1016/j.cell.2022.09.037.
Liming Yan 1,  Yucen Huang 2,  Ji Ge 3,  Zhenyu Liu 4,  Pengchi Lu 5,  Bo Huang 6,  Shan Gao 1,  Junbo Wang 1,  Liping Tan 1,  Sihan Ye 1,  Fengxi Yu 7,  Weiqi Lan 8,  Shiya Xu 1,  Feng Zhou 6,  Lei Shi 6,  Luke W Guddat 9,  Yan Gao 10,  Zihe Rao 11,  Zhiyong Lou 12
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, China.
  • 2 MOE Key Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, China; Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
  • 3 MOE Key Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, China; Innovation Center for Pathogen Research, Guangzhou Laboratory, Guangzhou, China.
  • 4 MOE Key Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, China; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 5 Division of Biosciences, University College London, London, UK.
  • 6 Beijing StoneWise Technology Co Ltd., Beijing, China.
  • 7 Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
  • 8 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 9 School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
  • 10 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China. Electronic address: [email protected].
  • 11 MOE Key Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, China; Innovation Center for Pathogen Research, Guangzhou Laboratory, Guangzhou, China; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China; State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and College of Pharmacy, Nankai University, Tianjin, China; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. Electronic address: [email protected].
  • 12 MOE Key Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, China. Electronic address: [email protected].
PMID: 36335936 DOI: 10.1016/j.cell.2022.09.037
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.

Keywords

SARS-CoV-2; capping; cryo-EM; nucleotide analog inhibitor.

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