The structural basis for RNA slicing by human Argonaute2. Mohamed et al.

This slicing drives post-transcriptional gene-silencing through RNA interference (RNAi), which is essential for many eukaryotes and the basis for new clinical therapies. Despite this importance, structural information on eukaryotic AGOs in a fully paired, slicing-competent conformation—hypothesized to be intrinsically unstable—has been lacking.

Here, we present the cryogenic-electron microscopy structure of a human AGO−guide complex bound to a fully paired target, revealing structural rearrangements that enable this conformation. Critically, the N domain of AGO rotates to allow the RNA full access to the central channel and forms contacts that license rapid slicing. Moreover, a conserved loop in the PIWI domain secures the RNA near the active site to enhance slicing rate and specificity.