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- EMDB-65663: AGO maturation complex (AMC): AGO2-miRNA duplex in complex with H... -

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Basic information

Entry
Database: EMDB / ID: EMD-65663
TitleAGO maturation complex (AMC): AGO2-miRNA duplex in complex with Hsp90 beta and co-chaperone p23
Map data
Sample
  • Complex: Complex of AGO2 with miRNA and Hsp90-p23
    • Protein or peptide: Heat shock protein HSP 90-beta
    • Protein or peptide: Prostaglandin E synthase 3
    • Protein or peptide: Protein argonaute-2
    • RNA: RNA (5'-R(P*UP*GP*AP*GP*GP*UP*AP*GP*UP*AP*GP*GP*UP*UP*GP*UP*AP*UP*AP*GP*UP*U)-3')
    • RNA: RNA (5'-R(P*CP*UP*AP*UP*AP*CP*AP*AP*UP*CP*UP*AP*CP*UP*GP*UP*CP*UP*UP*UP*CP*U)-3')
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
KeywordsHsp90 / p23 / Argonaute / miRNA / AGO2 / chaperone / co-chaperone
Function / homology
Function and homology information


prostaglandin-E synthase / prostaglandin-E synthase activity / HSP90-CDC37 chaperone complex / : / 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 ...prostaglandin-E synthase / prostaglandin-E synthase activity / HSP90-CDC37 chaperone complex / : / 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 / negative regulation of proteasomal protein catabolic process / Aryl hydrocarbon receptor signalling / Regulation of PTEN mRNA translation / miRNA-mediated gene silencing by mRNA destabilization / negative regulation of amyloid precursor protein biosynthetic process / RNA stabilization / telomerase activity / aryl hydrocarbon receptor complex / Small interfering RNA (siRNA) biogenesis / prostanoid biosynthetic process / Regulation of CDH1 mRNA translation by microRNAs / positive regulation of trophoblast cell migration / Transcriptional Regulation by MECP2 / histone methyltransferase binding / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / dynein axonemal particle / 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 / receptor ligand inhibitor activity / miRNA processing / RNA 7-methylguanosine cap binding / pre-miRNA processing / protein kinase regulator activity / regulation of synapse maturation / positive regulation of protein localization to cell surface / prostaglandin biosynthetic process / siRNA binding / mRNA 3'-UTR AU-rich region binding / M-decay: degradation of maternal mRNAs by maternally stored factors / siRNA processing / ATP-dependent protein binding / Regulation of MITF-M-dependent genes involved in apoptosis / RISC complex / TGFBR3 expression / regulatory ncRNA-mediated gene silencing / telomerase holoenzyme complex / 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 / Respiratory syncytial virus genome replication / telomerase holoenzyme complex assembly / Uptake and function of diphtheria toxin / positive regulation of transforming growth factor beta receptor signaling pathway / dendritic growth cone / TPR domain binding / Assembly and release of respiratory syncytial virus (RSV) virions / positive regulation of nuclear-transcribed mRNA poly(A) tail shortening / RNA polymerase II complex binding / Sema3A PAK dependent Axon repulsion / The NLRP3 inflammasome / regulation of protein ubiquitination / protein phosphatase activator activity / HSF1-dependent transactivation / protein folding chaperone complex / response to unfolded protein / Regulation of MECP2 expression and activity / Attenuation phase / HSF1 activation / chaperone-mediated protein complex assembly / axonal growth cone / RHOBTB2 GTPase cycle / telomere maintenance via telomerase / core promoter sequence-specific DNA binding / Purinergic signaling in leishmaniasis infection / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / positive regulation of telomere maintenance via telomerase / supramolecular fiber organization / heat shock protein binding / peptide binding / Nuclear events stimulated by ALK signaling in cancer / DNA polymerase binding / RNA endonuclease activity / translation initiation factor activity / protein folding chaperone / cellular response to interleukin-4 / ESR-mediated signaling / negative regulation of translational initiation / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / placenta development / telomere maintenance / nitric-oxide synthase regulator activity / post-embryonic development
Similarity search - Function
Co-chaperone protein p23-like / CS domain / CS domain / CS domain profile. / Protein argonaute-2 / Protein argonaute, Mid domain / Mid domain of argonaute / Argonaute linker 2 domain / Protein argonaute, N-terminal / Argonaute-like, PIWI domain ...Co-chaperone protein p23-like / CS domain / CS domain / CS domain profile. / 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 / HSP20-like chaperone / Piwi domain profile. / Piwi domain / Piwi domain / Piwi / PAZ domain superfamily / PAZ / PAZ domain / PAZ domain profile. / PAZ domain / Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / Hsp90 protein / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase / Histidine kinase/HSP90-like ATPase superfamily / Ribonuclease H superfamily / Ribonuclease H-like superfamily / Ribosomal protein S5 domain 2-type fold
Similarity search - Domain/homology
Heat shock protein HSP 90-beta / Prostaglandin E synthase 3 / Protein argonaute-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.63 Å
AuthorsLee H / Jeong M-S / Lee Y-Y / Lee J-H / Lee D / Kim VN / Roh S-H
Funding support Korea, Republic Of, 1 items
OrganizationGrant numberCountry
National Research Foundation (NRF, Korea) Korea, Republic Of
CitationJournal: Nature / Year: 2026
Title: Structural basis for chaperone-guided assembly of RNA-induced silencing complex.
Authors: Young-Yoon Lee / Minseok Jeong / Hansol Lee / Daniel Lee / Jaehyun Lee / Junsun Park / V Narry Kim / Soung-Hun Roh /
Abstract: The RNA-induced silencing complex (RISC), comprising an Argonaute (AGO) protein and a small RNA, is the central effector in RNA silencing. Small RNAs are loaded onto AGO as bulky duplexes in an HSP70- ...The RNA-induced silencing complex (RISC), comprising an Argonaute (AGO) protein and a small RNA, is the central effector in RNA silencing. Small RNAs are loaded onto AGO as bulky duplexes in an HSP70- and HSP90-dependent process, but the molecular mechanism remains poorly understood. Here we identify the human AGO-HSP90-p23 complex, which captures AGO in an RNA-free state, termed the AGO maturation complex (AMC). The purified AMC enables RNA loading and AGO folding, faithfully recapitulating de novo RISC assembly. Using cryogenic electron microscopy, we determined the structure of AMC bound to a microRNA duplex. In contrast to its conformation in the RISC, AGO adopts a highly open conformation in the AMC: the N domain and the RNA-binding module (PAZ-MID-PIWI) are fully detached and anchored to opposite sides of the HSP90 dimer, connected solely by the unfolded L1 linker. This arrangement exposes a positively charged cleft that accommodates an RNA duplex. AGO folding is facilitated by a small RNA duplex containing a 5'-terminal phosphate-but not by single-stranded RNAs-revealing a role for the RNA duplex as a chaperone-like cofactor that directs AGO domain assembly. These findings elucidate the RISC assembly mechanism and establish the AMC as a molecular tool for probing optimal RNA features and chemical modifications for the rational design of small interfering RNA therapeutics. Our study also sheds light on how chaperones, together with ligands, can guide the folding of client proteins.
History
DepositionAug 1, 2025-
Header (metadata) releaseApr 22, 2026-
Map releaseApr 22, 2026-
UpdateJul 1, 2026-
Current statusJul 1, 2026Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_65663.png

Downloads & links

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Map

FileDownload / File: emd_65663.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.14 Å/pix.
x 280 pix.
= 318.72 Å		1.14 Å/pix.
x 280 pix.
= 318.72 Å		1.14 Å/pix.
x 280 pix.
= 318.72 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.13829 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0834
Minimum - Maximum-0.94755596 - 2.4992652
Average (Standard dev.)-0.00053704926 (±0.032859344)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 318.71997 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Complex of AGO2 with miRNA and Hsp90-p23

EntireName: Complex of AGO2 with miRNA and Hsp90-p23
Components
  • Complex: Complex of AGO2 with miRNA and Hsp90-p23
    • Protein or peptide: Heat shock protein HSP 90-beta
    • Protein or peptide: Prostaglandin E synthase 3
    • Protein or peptide: Protein argonaute-2
    • RNA: RNA (5'-R(P*UP*GP*AP*GP*GP*UP*AP*GP*UP*AP*GP*GP*UP*UP*GP*UP*AP*UP*AP*GP*UP*U)-3')
    • RNA: RNA (5'-R(P*CP*UP*AP*UP*AP*CP*AP*AP*UP*CP*UP*AP*CP*UP*GP*UP*CP*UP*UP*UP*CP*U)-3')
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION

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Supramolecule #1: Complex of AGO2 with miRNA and Hsp90-p23

SupramoleculeName: Complex of AGO2 with miRNA and Hsp90-p23 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Heat shock protein HSP 90-beta

MacromoleculeName: Heat shock protein HSP 90-beta / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 83.38425 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPEEVHHGEE EVETFAFQAE IAQLMSLIIN TFYSNKEIFL RELISNASDA LDKIRYESLT DPSKLDSGKE LKIDIIPNPQ ERTLTLVDT GIGMTKADLI NNLGTIAKSG TKAFMEALQA GADISMIGQF GVGFYSAYLV AEKVVVITKH NDDEQYAWES S AGGSFTVR ...String:
MPEEVHHGEE EVETFAFQAE IAQLMSLIIN TFYSNKEIFL RELISNASDA LDKIRYESLT DPSKLDSGKE LKIDIIPNPQ ERTLTLVDT GIGMTKADLI NNLGTIAKSG TKAFMEALQA GADISMIGQF GVGFYSAYLV AEKVVVITKH NDDEQYAWES S AGGSFTVR ADHGEPIGRG TKVILHLKED QTEYLEERRV KEVVKKHSQF IGYPITLYLE KEREKEISDD EAEEEKGEKE EE DKDDEEK PKIEDVGSDE EDDSGKDKKK KTKKIKEKYI DQEELNKTKP IWTRNPDDIT QEEYGEFYKS LTNDWEDHLA VKH FSVEGQ LEFRALLFIP RRAPFDLFEN KKKKNNIKLY VRRVFIMDSC DELIPEYLNF IRGVVDSEDL PLNISREMLQ QSKI LKVIR KNIVKKCLEL FSELAEDKEN YKKFYEAFSK NLKLGIHEDS TNRRRLSELL RYHTSQSGDE MTSLSEYVSR MKETQ KSIY YITGESKEQV ANSAFVERVR KRGFEVVYMT EPIDEYCVQQ LKEFDGKSLV SVTKEGLELP EDEEEKKKME ESKAKF ENL CKLMKEILDK KVEKVTISNR LVSSPCCIVT STYGWTANME RIMKAQALRD NSTMGYMMAK KHLEINPDHP IVETLRQ KA EADKNDKAVK DLVVLLFETA LLSSGFSLED PQTHSNRIYR MIKLGLGIDE DEVAAEEPNA AVPDEIPPLE GDEDASRM E EVD

UniProtKB: Heat shock protein HSP 90-beta

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Macromolecule #2: Prostaglandin E synthase 3

MacromoleculeName: Prostaglandin E synthase 3 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: prostaglandin-E synthase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 18.720395 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MQPASAKWYD RRDYVFIEFC VEDSKDVNVN FEKSKLTFSC LGGSDNFKHL NEIDLFHCID PNDSKHKRTD RSILCCLRKG ESGQSWPRL TKERAKLNWL SVDFNNWKDW EDDSDEDMSN FDRFSEMMNN MGGDEDVDLP EVDGADDDSQ DSDDEKMPDL E

UniProtKB: Prostaglandin E synthase 3

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Macromolecule #3: Protein argonaute-2

MacromoleculeName: Protein argonaute-2 / type: protein_or_peptide / ID: 3 / 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: 97.350172 KDa
Recombinant expressionOrganism: Homo sapiens (human)
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 SFNTDPYVRE 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 EHDSAEGSHT SGQSNGRDHQ ALAKAVQVHQ DTLRTMYFA

UniProtKB: Protein argonaute-2

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Macromolecule #4: RNA (5'-R(P*UP*GP*AP*GP*GP*UP*AP*GP*UP*AP*GP*GP*UP*UP*GP*UP*AP*UP...

MacromoleculeName: RNA (5'-R(P*UP*GP*AP*GP*GP*UP*AP*GP*UP*AP*GP*GP*UP*UP*GP*UP*AP*UP*AP*GP*UP*U)-3')
type: rna / ID: 4 / Details: Human let-7a-1 5p strand / Number of copies: 1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.118211 KDa
SequenceString:
UGAGGUAGUA GGUUGUAUAG UU

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Macromolecule #5: RNA (5'-R(P*CP*UP*AP*UP*AP*CP*AP*AP*UP*CP*UP*AP*CP*UP*GP*UP*CP*UP...

MacromoleculeName: RNA (5'-R(P*CP*UP*AP*UP*AP*CP*AP*AP*UP*CP*UP*AP*CP*UP*GP*UP*CP*UP*UP*UP*CP*U)-3')
type: rna / ID: 5 / Details: Human let-7a-1 3p strand / Number of copies: 1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 6.839026 KDa
SequenceString:
CUAUACAAUC UACUGUCUUU CU

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Macromolecule #6: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 6 / Number of copies: 2 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

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Macromolecule #7: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 7 / Number of copies: 3 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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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

BufferpH: 8
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 288 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 69.9 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.7 µm / Nominal defocus min: 0.7000000000000001 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.63 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 1225410
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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