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Structure paper

TitleCatalytic activation of human Argonaute 2 requires RNA duplex deformation.
Journal, issue, pagesNat. Struct. Mol. Biol., Year 2026
Publish dateFeb 23, 2026
AuthorsSucharita Sarkar / Luca F R Gebert / Ian J MacRae /
PubMed AbstractSmall 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, ...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.
External linksNat. Struct. Mol. Biol. / PubMed:42342972
MethodsEM (single particle)
Resolution3.0 - 3.3 Å
Structure data

46888

9dhx

EMDB-46888: human Argonaute-2 R315V/H316A - miR-122 in complex with a fully complementary target
PDB-9dhx: human Argonaute2 R315V/H316A - guide RNA in complex with a fully complementary target
Method: EM (single particle) / Resolution: 3.1 Å

75677

11gi

EMDB-75677, PDB-11gi:
Human Argonaute2 WT - guide(3 prime-amino) RNA in complex with a fully complementary target
Method: EM (single particle) / Resolution: 3.0 Å

75678

11gj

EMDB-75678, PDB-11gj:
Human Argonaute2 R315V/H316A - guide10U RNA in complex with a complementary target to position 19
Method: EM (single particle) / Resolution: 3.3 Å

75679

11gk

EMDB-75679, PDB-11gk:
Human Argonaute2 R315V/H316A - guide RNA in complex with a fully complementary target (conformation 2)
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsRNA BINDING PROTEIN/RNA / RNA binding protein / RNP / RNA / Argonaute2 / Ago2 / RNA BINDING PROTEIN-RNA complex

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