Structural basis of ribosomal frameshifting during translation of the SARS-CoV-2 RNA genome.

Details

Serval ID
serval:BIB_AA30EA09AC1E
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Structural basis of ribosomal frameshifting during translation of the SARS-CoV-2 RNA genome.
Journal
Science
Author(s)
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.
ISSN
1095-9203 (Electronic)
ISSN-L
0036-8075
Publication state
Published
Issued date
18/06/2021
Peer-reviewed
Oui
Volume
372
Number
6548
Pages
1306-1313
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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.
Keywords
Animals, Antiviral Agents/pharmacology, Codon, Terminator, Coronavirus RNA-Dependent RNA Polymerase/biosynthesis, Coronavirus RNA-Dependent RNA Polymerase/chemistry, Coronavirus RNA-Dependent RNA Polymerase/genetics, Cryoelectron Microscopy, Fluoroquinolones/pharmacology, Frameshifting, Ribosomal/drug effects, Genome, Viral, Humans, Image Processing, Computer-Assisted, Models, Molecular, Nucleic Acid Conformation, Open Reading Frames, Protein Folding, RNA, Messenger/chemistry, RNA, Messenger/genetics, RNA, Messenger/metabolism, RNA, Ribosomal, 18S/chemistry, RNA, Ribosomal, 18S/genetics, RNA, Ribosomal, 18S/metabolism, RNA, Viral/chemistry, RNA, Viral/genetics, RNA, Viral/metabolism, Ribosomal Proteins/metabolism, Ribosomes/metabolism, Ribosomes/ultrastructure, SARS-CoV-2/drug effects, SARS-CoV-2/genetics, SARS-CoV-2/physiology, Viral Proteins/biosynthesis, Viral Proteins/chemistry, Viral Proteins/genetics, Virus Replication/drug effects
Pubmed
Web of science
Open Access
Yes
Funding(s)
Swiss National Science Foundation / 31003A_182341
Swiss National Science Foundation / 182880
Swiss National Science Foundation / 310030_173085
Create date
27/05/2021 13:28
Last modification date
14/08/2021 5:35
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