The NCCR RNA & Disease groups of Nenad Ban (ETH Zurich) and Volker Thiel (University of Bern) together with the groups of John Atkins (University College Cork, Ireland) and Jeffrey Bode (ETH Zurich) joined forces to gain structural insights into translational frameshifting on the SARS-CoV-2 RNA genome, which is an important step in its translation. They complemented their structural findings with biochemical experiments and could demonstrate that a compound reducing frameshifting can inhibit viral replication in cells. They posted their preprint on bioRxiv.
Programmed ribosomal frameshifting is the key event during translation of the SARS-CoV-2 RNA genome allowing synthesis of the viral RNA-dependent RNA polymerase and downstream viral proteins. Here we present the cryo-EM structure of the mammalian ribosome in the process of translating viral RNA paused in a conformation primed for frameshifting. We observe that the viral RNA adopts a pseudoknot structure lodged at the mRNA entry channel of the ribosome to generate tension in the mRNA that leads to frameshifting. The nascent viral polyprotein that is being synthesized by the ribosome paused at the frameshifting site forms distinct interactions with the ribosomal polypeptide exit tunnel. We use biochemical experiments to validate our structural observations and to reveal mechanistic and regulatory features that influence the frameshifting efficiency. Finally, a compound previously shown to reduce frameshifting is able to inhibit SARS-CoV-2 replication in infected cells, establishing coronavirus frameshifting as target for antiviral intervention.
Figure 5 and abstract from Bhatt, Scaiola et al. (2020) Structural basis of ribosomal frameshifting during translation of the SARS-CoV-2 RNA genome posted on bioRxiv. Published under a CC BY-NC-ND 4.0 license.