11GJ

Human Argonaute2 R315V/H316A - guide10U RNA in complex with a complementary target to position 19

Summary for 11GJ

• Entry DOI: 10.2210/pdb11gj/pdb
• Related: 11GJ 11GK 9DHX
• EMDB information: 75678
• Descriptor: Argonaute2 R315V/H316A, guide RNA (g10U), target RNA (t10A), ... (4 entities in total)
• Functional Keywords: rna binding protein, rnp, rna, argonaute2, ago2, rna binding protein-rna complex, rna binding protein/rna
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 112641.60

Authors

Sarkar, S.,Gebert, L.F.R.,MacRae, I.J. (deposition date: 2026-02-23, release date: 2026-05-13, Last modification date: 2026-07-08)

Primary citation

Sarkar, S.,Gebert, L.F.R.,MacRae, I.J.
Catalytic activation of human Argonaute 2 requires RNA duplex deformation.
Nat.Struct.Mol.Biol., 2026

PubMed Abstract: Small interfering RNAs (siRNAs) are an expanding class of RNA therapeutics, with seven drugs approved by the US Food and Drug Administration and many more in development. Rational design, however, has been limited by incomplete understanding of how human Argonaute 2 (hAgo2) catalyzes target cleavage. Here we report high-resolution cryo-electron microscopy structures of hAgo2 bound to a target RNA in catalytic and noncatalytic conformations. The structures reveal that guide-target pairing alone is insufficient for slicing and catalysis requires deformation of the duplex through a coordinated network of RNA-protein interactions. Expansion of the central major groove positions the scissile phosphate, while compression toward the supplementary region docks the duplex into the hAgo2 cleft. A kink after guide nucleotide g6 disrupts seed-only pairing conformation and promotes the extended pairing required for catalysis. This rearrangement enables repositioning of K709 within the active site, while a pyrimidine at target position t10 optimally aligns R710 to accelerate cleavage. These findings provide a structural framework linking siRNA duplex geometry to catalytic efficiency and inform rational design of siRNAs with improved potency and specificity.

PubMed: 42342972
DOI: 10.1038/s41594-026-01840-5

Experimental method

ELECTRON MICROSCOPY (3.3 Å)