Science.: co-auth.: group Gatfield

Science. 2021 May 13;eabf3546. doi: 10.1126/science.abf3546. Online ahead of print.

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

Pramod R Bhatt # 1 2 3Alain Scaiola # 1Gary Loughran 2Marc Leibundgut 1Annika Kratzel 4 5 6Romane Meurs 7René Dreos 7Kate M O’Connor 2Angus McMillan 8Jeffrey W Bode 8Volker Thiel 4 5David Gatfield 7John F Atkins 9 3 10Nenad 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.