Science. 2021 May 13;eabf3546. doi: 10.1126/science.abf3546. Online ahead of print.
Pramod R Bhatt # 1 2 3, Alain Scaiola # 1, Gary Loughran 2, Marc Leibundgut 1, Annika Kratzel 4 5 6, Romane Meurs 7, René Dreos 7, Kate M O’Connor 2, Angus McMillan 8, Jeffrey W Bode 8, Volker Thiel 4 5, David Gatfield 7, John F Atkins 9 3 10, Nenad Ban 11Affiliations expand
Programmed ribosomal frameshifting is a key event during translation of the SARS-CoV-2 RNA genome allowing 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 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.
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).
- PMID: 34029205
- DOI: 10.1126/science.abf3546