9CMP

The structural basis for RNA slicing by human Argonaute2

Summary for 9CMP

• Entry DOI: 10.2210/pdb9cmp/pdb
• EMDB information: 45752
• Descriptor: RNA (5'-R(P*UP*GP*GP*AP*AP*GP*AP*CP*UP*AP*GP*UP*GP*AP*UP*UP*UP*UP*GP*UP*U)-3'), RNA (5'-R(*CP*AP*AP*CP*AP*AP*AP*AP*UP*CP*AP*CP*UP*AP*GP*UP*CP*UP*UP*CP*CP*A)-3'), Protein argonaute-2, ... (4 entities in total)
• Functional Keywords: rnai, argonaute, slicing, hydrolase-rna complex, hydrolase/rna
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 113234.87

Authors

Mohamed, A.A.,Wang, P.Y.,Bartel, D.P.,Vos, S.M. (deposition date: 2024-07-15, release date: 2024-12-11)

Primary citation

Mohamed, A.A.,Wang, P.Y.,Bartel, D.P.,Vos, S.M.
The structural basis for RNA slicing by human Argonaute2.
Biorxiv, 2024

PubMed Abstract: Argonaute (AGO) proteins associate with guide RNAs to form complexes that slice transcripts that pair to the guide. This slicing drives post-transcriptional gene-silencing pathways that are 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. These results explain how AGO accommodates targets possessing the pairing specificity typically observed in biological and clinical slicing substrates.

PubMed: 39229170
DOI: 10.1101/2024.08.19.608718

Experimental method

ELECTRON MICROSCOPY (3.3 Å)