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- EMDB-75677: Human Argonaute2 WT - guide(3 prime-amino) RNA in complex with a ... -

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Basic information

Entry
Database: EMDB / ID: EMD-75677
TitleHuman Argonaute2 WT - guide(3 prime-amino) RNA in complex with a fully complementary target
Map data
Sample
  • Complex: human Argonaute-2 - miR-122(3'-amino) in complex with a fully complementary target
    • Protein or peptide: Argonaute2 WT
    • RNA: guide(3 prime-amino) RNA
    • RNA: target RNA
  • Ligand: MAGNESIUM ION
  • Ligand: water
KeywordsRNA binding protein / RNP / RNA / Argonaute2 / Ago2 / RNA BINDING PROTEIN-RNA complex
Function / homology
Function and homology information


: / endoribonuclease activity, cleaving miRNA-paired mRNA / endoribonuclease activity, cleaving siRNA-paired mRNA / siRNA-mediated gene silencing by mRNA destabilization / Post-transcriptional silencing by small RNAs / Competing endogenous RNAs (ceRNAs) regulate PTEN translation / Regulation of CDH11 mRNA translation by microRNAs / Regulation of NPAS4 mRNA translation / Regulation of PTEN mRNA translation / miRNA-mediated gene silencing by mRNA destabilization ...: / endoribonuclease activity, cleaving miRNA-paired mRNA / endoribonuclease activity, cleaving siRNA-paired mRNA / siRNA-mediated gene silencing by mRNA destabilization / Post-transcriptional silencing by small RNAs / Competing endogenous RNAs (ceRNAs) regulate PTEN translation / Regulation of CDH11 mRNA translation by microRNAs / Regulation of NPAS4 mRNA translation / Regulation of PTEN mRNA translation / miRNA-mediated gene silencing by mRNA destabilization / negative regulation of amyloid precursor protein biosynthetic process / RNA stabilization / Small interfering RNA (siRNA) biogenesis / Regulation of CDH1 mRNA translation by microRNAs / positive regulation of trophoblast cell migration / Transcriptional Regulation by MECP2 / RISC-loading complex / miRNA metabolic process / mRNA cap binding / RISC complex assembly / regulatory ncRNA-mediated post-transcriptional gene silencing / miRNA-mediated gene silencing by inhibition of translation / miRNA processing / RNA 7-methylguanosine cap binding / pre-miRNA processing / regulation of synapse maturation / siRNA binding / mRNA 3'-UTR AU-rich region binding / M-decay: degradation of maternal mRNAs by maternally stored factors / siRNA processing / Regulation of MITF-M-dependent genes involved in apoptosis / RISC complex / TGFBR3 expression / regulatory ncRNA-mediated gene silencing / Regulation of RUNX1 Expression and Activity / P-body assembly / miRNA binding / MicroRNA (miRNA) biogenesis / positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay / positive regulation of nuclear-transcribed mRNA poly(A) tail shortening / RNA polymerase II complex binding / Regulation of MECP2 expression and activity / core promoter sequence-specific DNA binding / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / Nuclear events stimulated by ALK signaling in cancer / RNA endonuclease activity / translation initiation factor activity / negative regulation of translational initiation / post-embryonic development / TP53 Regulates Metabolic Genes / positive regulation of translation / Transcriptional regulation by small RNAs / P-body / MAPK6/MAPK4 signaling / Pre-NOTCH Transcription and Translation / positive regulation of angiogenesis / cytoplasmic ribonucleoprotein granule / double-stranded RNA binding / Ca2+ pathway / Estrogen-dependent gene expression / single-stranded RNA binding / postsynapse / translation / dendrite / glutamatergic synapse / positive regulation of transcription by RNA polymerase II / RNA binding / extracellular exosome / nucleoplasm / membrane / metal ion binding / nucleus / cytoplasm / cytosol
Similarity search - Function
Protein argonaute-2 / Protein argonaute, Mid domain / Mid domain of argonaute / Argonaute linker 2 domain / Protein argonaute, N-terminal / Argonaute-like, PIWI domain / N-terminal domain of argonaute / Argonaute linker 2 domain / DUF1785 / Argonaute, linker 1 domain ...Protein argonaute-2 / Protein argonaute, Mid domain / Mid domain of argonaute / Argonaute linker 2 domain / Protein argonaute, N-terminal / Argonaute-like, PIWI domain / N-terminal domain of argonaute / Argonaute linker 2 domain / DUF1785 / Argonaute, linker 1 domain / Argonaute linker 1 domain / Piwi domain profile. / Piwi domain / Piwi domain / Piwi / PAZ domain superfamily / PAZ / PAZ domain / PAZ domain profile. / PAZ domain / Ribonuclease H superfamily / Ribonuclease H-like superfamily
Similarity search - Domain/homology
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsSarkar S / Gebert LFR / MacRae IJ
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)5R35GM127090 United States
CitationJournal: Nat Struct Mol Biol / Year: 2026
Title: Catalytic activation of human Argonaute 2 requires RNA duplex deformation.
Authors: Sucharita Sarkar / Luca F R Gebert / Ian J MacRae /
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, ...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.
History
DepositionFeb 23, 2026-
Header (metadata) releaseMay 13, 2026-
Map releaseMay 13, 2026-
UpdateJul 8, 2026-
Current statusJul 8, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_75677.png

Downloads & links

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Map

FileDownload / File: emd_75677.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.74 Å/pix.
x 300 pix.
= 222. Å		0.74 Å/pix.
x 300 pix.
= 222. Å		0.74 Å/pix.
x 300 pix.
= 222. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.74 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.90143746 - 1.5089965
Average (Standard dev.)-0.000023281353 (±0.03440093)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 222.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_75677_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_75677_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : human Argonaute-2 - miR-122(3'-amino) in complex with a fully com...

EntireName: human Argonaute-2 - miR-122(3'-amino) in complex with a fully complementary target
Components
  • Complex: human Argonaute-2 - miR-122(3'-amino) in complex with a fully complementary target
    • Protein or peptide: Argonaute2 WT
    • RNA: guide(3 prime-amino) RNA
    • RNA: target RNA
  • Ligand: MAGNESIUM ION
  • Ligand: water

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Supramolecule #1: human Argonaute-2 - miR-122(3'-amino) in complex with a fully com...

SupramoleculeName: human Argonaute-2 - miR-122(3'-amino) in complex with a fully complementary target
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Argonaute2 WT

MacromoleculeName: Argonaute2 WT / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
EC number: Hydrolases; Acting on ester bonds; Endoribonucleases producing 5'-phosphomonoesters
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 97.402195 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MYSGAGPALA PPAPPPPIQG YAFKPPPRPD FGTSGRTIKL QANFFEMDIP KIDIYHYELD IKPEKCPRRV NREIVEHMVQ HFKTQIFGD RKPVFDGRKN LYTAMPLPIG RDKVELEVTL PGEGKDRIFK VSIKWVSCVS LQALHDALSG RLPSVPFETI Q ALDVVMRH ...String:
MYSGAGPALA PPAPPPPIQG YAFKPPPRPD FGTSGRTIKL QANFFEMDIP KIDIYHYELD IKPEKCPRRV NREIVEHMVQ HFKTQIFGD RKPVFDGRKN LYTAMPLPIG RDKVELEVTL PGEGKDRIFK VSIKWVSCVS LQALHDALSG RLPSVPFETI Q ALDVVMRH LPSMRYTPVG RSFFTASEGC SNPLGGGREV WFGFHQSVRP SLWKMMLNID VSATAFYKAQ PVIEFVCEVL DF KSIEEQQ KPLTDSQRVK FTKEIKGLKV EITHCGQMKR KYRVCNVTRR PASHQTFPLQ QESGQTVECT VAQYFKDRHK LVL RYPHLP CLQVGQEQKH TYLPLEVCNI VAGQRCIKKL TDNQTSTMIR ATARSAPDRQ EEISKLMRSA DFNTDPYVRE FGIM VKDEM TDVTGRVLQP PSILYGGRNK AIATPVQGVW DMRNKQFHTG IEIKVWAIAC FAPQRQCTEV HLKSFTEQLR KISRD AGMP IQGQPCFCKY AQGADSVEPM FRHLKNTYAG LQLVVVILPG KTPVYAEVKR VGDTVLGMAT QCVQMKNVQR TTPQTL SNL CLKINVKLGG VNNILLPQGR PPVFQQPVIF LGADVTHPPA GDGKKPSIAA VVGSMDAHPN RYCATVRVQQ HRQEIIQ DL AAMVRELLIQ FYKSTRFKPT RIIFYRDGVS EGQFQQVLHH ELLAIREACI KLEKDYQPGI TFIVVQKRHH TRLFCTDK N ERVGKSGNIP AGTTVDTKIT HPTEFDFYLC SHAGIQGTSR PSHYHVLWDD NRFSSDELQI LTYQLCHTYV RCTRSVSIP APAYYAHLVA FRARYHLVDK EHDAAEGDHT DGQANGRDHQ ALAKAVQVHQ DTLRTMYFA

UniProtKB: Protein argonaute-2

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Macromolecule #2: guide(3 prime-amino) RNA

MacromoleculeName: guide(3 prime-amino) RNA / type: rna / ID: 2 / Number of copies: 1
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 6.481856 KDa
SequenceString:
UGGAGUGUGA CAAUGGUGUU

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Macromolecule #3: target RNA

MacromoleculeName: target RNA / type: rna / ID: 3 / Number of copies: 1
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 7.258423 KDa
SequenceString:
AAACACCAUU GUCACACUCC AAA

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Macromolecule #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 1 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 2 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1.2 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
50.0 mMTRISTRIS
100.0 mMNaClNaCl
0.5 mMTCEPTCEP
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number grids imaged: 6 / Number real images: 20132 / Average exposure time: 3.2 sec. / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: OTHER / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 190000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC (ver. 4.7) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.7) / Number images used: 207140
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final 3D classificationSoftware - Name: cryoSPARC (ver. 4.7)

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Atomic model buiding 1

Initial modelPDB ID:

6n4o


Chain - Chain ID: A / Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-11gi:
Human Argonaute2 WT - guide(3 prime-amino) RNA in complex with a fully complementary target

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