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Structural basis of ribosomal frameshifting during translation of the SARS-CoV-2 RNA genome.
Science. 2021 06 18; 372(6548):1306-1313.Sci

Abstract

Programmed ribosomal frameshifting is a key event during translation of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA genome that allows synthesis of the viral RNA-dependent RNA polymerase and downstream proteins. Here, we present the cryo-electron microscopy structure of a translating mammalian ribosome primed for frameshifting on the viral RNA. The viral RNA adopts a pseudoknot structure that lodges at the entry to the ribosomal messenger RNA (mRNA) channel to generate tension in the mRNA and promote frameshifting, whereas the nascent viral polyprotein forms distinct interactions with the ribosomal tunnel. Biochemical experiments validate the structural observations and reveal mechanistic and regulatory features that influence frameshifting efficiency. Finally, we compare compounds previously shown to reduce frameshifting with respect to their ability to inhibit SARS-CoV-2 replication, establishing coronavirus frameshifting as a target for antiviral intervention.

Authors+Show Affiliations

Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland. School of Biochemistry and Cell Biology, University College Cork, Cork T12 XF62, Ireland. School of Microbiology, University College Cork, Cork T12 K8AF, Ireland.Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland.School of Biochemistry and Cell Biology, University College Cork, Cork T12 XF62, Ireland.Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland.Institute of Virology and Immunology, University of Bern, Bern, Switzerland. Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland. Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.Center for Integrative Genomics, Génopode, University of Lausanne, 1015 Lausanne, Switzerland.Center for Integrative Genomics, Génopode, University of Lausanne, 1015 Lausanne, Switzerland.School of Biochemistry and Cell Biology, University College Cork, Cork T12 XF62, Ireland.Laboratorium für Organische Chemie, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.Laboratorium für Organische Chemie, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.Institute of Virology and Immunology, University of Bern, Bern, Switzerland. Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.Center for Integrative Genomics, Génopode, University of Lausanne, 1015 Lausanne, Switzerland.School of Biochemistry and Cell Biology, University College Cork, Cork T12 XF62, Ireland. j.atkins@ucc.ie ban@mol.biol.ethz.ch. School of Microbiology, University College Cork, Cork T12 K8AF, Ireland. MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland. j.atkins@ucc.ie ban@mol.biol.ethz.ch.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34029205

Citation

Bhatt, Pramod R., et al. "Structural Basis of Ribosomal Frameshifting During Translation of the SARS-CoV-2 RNA Genome." Science (New York, N.Y.), vol. 372, no. 6548, 2021, pp. 1306-1313.
Bhatt PR, Scaiola A, Loughran G, et al. Structural basis of ribosomal frameshifting during translation of the SARS-CoV-2 RNA genome. Science. 2021;372(6548):1306-1313.
Bhatt, P. R., Scaiola, A., Loughran, G., Leibundgut, M., Kratzel, A., Meurs, R., Dreos, R., O'Connor, K. M., McMillan, A., Bode, J. W., Thiel, V., Gatfield, D., Atkins, J. F., & Ban, N. (2021). Structural basis of ribosomal frameshifting during translation of the SARS-CoV-2 RNA genome. Science (New York, N.Y.), 372(6548), 1306-1313. https://doi.org/10.1126/science.abf3546
Bhatt PR, et al. Structural Basis of Ribosomal Frameshifting During Translation of the SARS-CoV-2 RNA Genome. Science. 2021 06 18;372(6548):1306-1313. PubMed PMID: 34029205.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structural basis of ribosomal frameshifting during translation of the SARS-CoV-2 RNA genome. AU - Bhatt,Pramod R, AU - Scaiola,Alain, AU - Loughran,Gary, AU - Leibundgut,Marc, AU - Kratzel,Annika, AU - Meurs,Romane, AU - Dreos,René, AU - O'Connor,Kate M, AU - McMillan,Angus, AU - Bode,Jeffrey W, AU - Thiel,Volker, AU - Gatfield,David, AU - Atkins,John F, AU - Ban,Nenad, Y1 - 2021/05/13/ PY - 2020/10/20/received PY - 2021/02/24/revised PY - 2021/05/07/accepted PY - 2021/5/25/pubmed PY - 2021/7/3/medline PY - 2021/5/24/entrez SP - 1306 EP - 1313 JF - Science (New York, N.Y.) JO - Science VL - 372 IS - 6548 N2 - Programmed ribosomal frameshifting is a key event during translation of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA genome that allows synthesis of the viral RNA-dependent RNA polymerase and downstream proteins. Here, we present the cryo-electron microscopy structure of a translating mammalian ribosome primed for frameshifting on the viral RNA. The viral RNA adopts a pseudoknot structure that lodges at the entry to the ribosomal messenger RNA (mRNA) channel to generate tension in the mRNA and promote frameshifting, whereas the nascent viral polyprotein forms distinct interactions with the ribosomal tunnel. Biochemical experiments validate the structural observations and reveal mechanistic and regulatory features that influence frameshifting efficiency. Finally, we compare compounds previously shown to reduce frameshifting with respect to their ability to inhibit SARS-CoV-2 replication, establishing coronavirus frameshifting as a target for antiviral intervention. SN - 1095-9203 UR - https://www.unboundmedicine.com/medline/citation/34029205/Structural_basis_of_ribosomal_frameshifting_during_translation_of_the_SARS-CoV-2_RNA_genome. L2 - https://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=34029205 DB - PRIME DP - Unbound Medicine ER -