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- PDB-9rwz: ZSWIM8-CUL3 complex bound to AGO2-miR-7-CYRANO -

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Basic information

Entry
Database: PDB / ID: 9rwz
TitleZSWIM8-CUL3 complex bound to AGO2-miR-7-CYRANO
Components
  • CYRANO trigger RNA
  • Cullin-3
  • Elongin-B
  • Elongin-C
  • Protein argonaute-2
  • Zinc finger SWIM domain-containing protein 8
  • miR-7
KeywordsLIGASE / miRNA / E3 Ligase
Function / homology
Function and homology information


positive regulation of miRNA catabolic process / positive regulation of mitotic cell cycle phase transition / trophectodermal cellular morphogenesis / liver morphogenesis / POZ domain binding / : / 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 ...positive regulation of miRNA catabolic process / positive regulation of mitotic cell cycle phase transition / trophectodermal cellular morphogenesis / liver morphogenesis / POZ domain binding / : / 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 / polar microtubule / Small interfering RNA (siRNA) biogenesis / regulation protein catabolic process at postsynapse / positive regulation of trophoblast cell migration / Regulation of CDH1 mRNA translation by microRNAs / anaphase-promoting complex-dependent catabolic process / nuclear protein quality control by the ubiquitin-proteasome system / COPII vesicle coat assembly / Transcriptional Regulation by MECP2 / RISC-loading complex / miRNA metabolic process / mRNA cap binding / RHOBTB3 ATPase cycle / RISC complex assembly / regulatory ncRNA-mediated post-transcriptional gene silencing / miRNA-mediated gene silencing by inhibition of translation / miRNA processing / embryonic cleavage / RNA 7-methylguanosine cap binding / pre-miRNA processing / regulation of synapse maturation / siRNA processing / siRNA binding / mRNA 3'-UTR AU-rich region binding / M-decay: degradation of maternal mRNAs by maternally stored factors / Regulation of MITF-M-dependent genes involved in apoptosis / target-directed miRNA degradation / positive regulation of mitotic metaphase/anaphase transition / elongin complex / RISC complex / TGFBR3 expression / fibroblast apoptotic process / Notch binding / regulatory ncRNA-mediated gene silencing / Regulation of RUNX1 Expression and Activity / cell projection organization / negative regulation of Rho protein signal transduction / P-body assembly / RHOBTB1 GTPase cycle / miRNA binding / VCB complex / MicroRNA (miRNA) biogenesis / Cul5-RING ubiquitin ligase complex / stem cell division / positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / mitotic metaphase chromosome alignment / Cul2-RING ubiquitin ligase complex / stress fiber assembly / Cul3-RING ubiquitin ligase complex / negative regulation of type I interferon production / positive regulation of cytokinesis / positive regulation of nuclear-transcribed mRNA poly(A) tail shortening / ubiquitin ligase complex scaffold activity / RNA polymerase II complex binding / protein quality control for misfolded or incompletely synthesized proteins / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / Regulation of MECP2 expression and activity / endoplasmic reticulum to Golgi vesicle-mediated transport / protein monoubiquitination / Tat-mediated elongation of the HIV-1 transcript / RHOBTB2 GTPase cycle / sperm flagellum / Formation of HIV-1 elongation complex containing HIV-1 Tat / core promoter sequence-specific DNA binding / Formation of HIV elongation complex in the absence of HIV Tat / protein autoubiquitination / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / ubiquitin-like ligase-substrate adaptor activity / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / Nuclear events stimulated by ALK signaling in cancer / protein K48-linked ubiquitination / RNA endonuclease activity / translation initiation factor activity / RNA Polymerase II Pre-transcription Events / gastrulation / regulation of cellular response to insulin stimulus / positive regulation of TORC1 signaling / negative regulation of translational initiation
Similarity search - Function
: / : / ZSWIM4-8, C-terminal / ZSWIM8, TPR repeats / Zinc finger, SWIM-type / Zinc finger SWIM-type profile. / Protein argonaute-2 / Protein argonaute, Mid domain / Mid domain of argonaute / Argonaute linker 2 domain ...: / : / ZSWIM4-8, C-terminal / ZSWIM8, TPR repeats / Zinc finger, SWIM-type / Zinc finger SWIM-type 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 / Piwi domain profile. / Piwi domain / Piwi domain / Piwi / PAZ domain superfamily / PAZ / PAZ domain / Cullin, N-terminal / Cullin protein neddylation domain / Cullin, conserved site / Cullin alpha solenoid domain / Cullin family signature. / Elongin-C / Elongin B / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / Cullin / Cullin protein neddylation domain / PAZ domain profile. / PAZ domain / Cullin / : / Cullin alpha+beta domain / Cullin homology domain / Cullin homology domain superfamily / Cullin family profile. / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / SKP1/BTB/POZ domain superfamily / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ribonuclease H superfamily / Ribonuclease H-like superfamily / Ubiquitin-like domain superfamily / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
: / RNA / RNA (> 10) / RNA (> 100) / Zinc finger SWIM domain-containing protein 8 / Cullin-3 / Elongin-C / Elongin-B / Protein argonaute-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsFarnung, J. / Slobodyanyuk, E. / Bartel, D.P. / Schulman, B.A.
Funding supportEuropean Union, Germany, 2items
OrganizationGrant numberCountry
European Research Council (ERC)101098161European Union
German Research Foundation (DFG) Germany
CitationJournal: Nature / Year: 2026
Title: The E3 ubiquitin ligase mechanism specifying targeted microRNA degradation.
Authors: Jakob Farnung / Elena Slobodyanyuk / Peter Y Wang / Lianne W Blodgett / Daniel H Lin / Susanne von Gronau / Brenda A Schulman / David P Bartel /
Abstract: MicroRNAs (miRNAs) associate with Argonaute (AGO) proteins to form complexes that down-regulate target RNAs, including messenger RNAs from most human genes. Within each complex, the miRNA pairs to ...MicroRNAs (miRNAs) associate with Argonaute (AGO) proteins to form complexes that down-regulate target RNAs, including messenger RNAs from most human genes. Within each complex, the miRNA pairs to target RNAs, and AGO provides effector function while also protecting the miRNA from cellular nucleases. Although much is known about miRNA-directed gene regulation, less is known about how miRNAs themselves are regulated. One pathway that regulates miRNAs involves unusual targets called 'trigger' RNAs, which reverse the canonical regulatory logic and instead down-regulate miRNAs. This target-directed miRNA degradation (TDMD) is thought to require a cullin-RING E3 ligase because it depends on the cullin protein CUL3 and other ubiquitylation components, including the BC-box protein ZSWIM8 (refs. ). ZSWIM8 is required for murine perinatal viability and for destabilization of most short-lived miRNAs, which suggests biological importance of TDMD. Here, biochemical and cellular assays establish AGO binding and polyubiquitylation by the ZSWIM8-CUL3 E3 ligase as the key regulatory steps of TDMD, and thereby define a unique cullin-RING E3 ligase class. Cryogenic electron microscopy analyses show ZSWIM8 recognizing distinct AGO and RNA conformations shaped by pairing of the miRNA to the trigger. Specificity of AGO ubiquitylation is established through generalizable RNA-RNA, RNA-protein and protein-protein interactions. The substrate features recognized by the E3 ligase do not conform to a conventional degron but instead establish a two-RNA-factor authentication mechanism for specifying a protein ubiquitylation substrate.
History
DepositionJul 10, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 18, 2026Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
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Revision 1.1Apr 1, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Protein argonaute-2
B: Elongin-B
C: Elongin-B
D: Elongin-C
E: Elongin-C
G: miR-7
H: Cullin-3
I: Cullin-3
T: CYRANO trigger RNA
N: Zinc finger SWIM domain-containing protein 8
M: Zinc finger SWIM domain-containing protein 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)689,95613
Polymers689,82511
Non-polymers1312
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 5 types, 9 molecules ABCDEHINM

#1: Protein Protein argonaute-2 / Argonaute2 / hAgo2 / Argonaute RISC catalytic component 2 / Eukaryotic translation initiation ...Argonaute2 / hAgo2 / Argonaute RISC catalytic component 2 / Eukaryotic translation initiation factor 2C 2 / eIF-2C 2 / eIF2C 2 / PAZ Piwi domain protein / PPD / Protein slicer


Mass: 98554.383 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: N-terminal hexahistidine purification tag was not removed.
Source: (gene. exp.) Homo sapiens (human) / Gene: AGO2, EIF2C2
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
References: UniProt: Q9UKV8, Hydrolases; Acting on ester bonds; Endoribonucleases producing 5'-phosphomonoesters
#2: Protein Elongin-B / EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / ...EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / Transcription elongation factor B polypeptide 2


Mass: 13147.781 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOB, TCEB2
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
References: UniProt: Q15370
#3: Protein Elongin-C / EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / ...EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / Transcription elongation factor B polypeptide 1


Mass: 12485.135 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
References: UniProt: Q15369
#5: Protein Cullin-3 / CUL-3


Mass: 46410.113 Da / Num. of mol.: 2 / Mutation: I342R, L346D
Source method: isolated from a genetically manipulated source
Details: CUL3 NTD containing solubilizing mutations I342R, L346D, and remnant of C-terminal TEV protease cleavage site.
Source: (gene. exp.) Homo sapiens (human) / Gene: CUL3, KIAA0617 / Production host: Escherichia coli (E. coli) / References: UniProt: Q13618
#7: Protein Zinc finger SWIM domain-containing protein 8


Mass: 200458.016 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: C-terminal twin-strep purification tag was not removed.
Source: (gene. exp.) Homo sapiens (human) / Gene: ZSWIM8, KIAA0913 / Production host: Spodoptera (butterflies/moths) / References: UniProt: A7E2V4

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RNA chain , 2 types, 2 molecules GT

#4: RNA chain miR-7


Mass: 7690.520 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: 5' terminus is phosphorylated / Source: (synth.) Homo sapiens (human)
#6: RNA chain CYRANO trigger RNA


Mass: 38577.793 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: GenBank: 2994212338

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Non-polymers , 1 types, 2 molecules

#8: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn

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Details

Has ligand of interestN
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: CYRANO-AGO2-miR-7 in complex with ZSWIM8-ELONGIN B/C, CUL3
Type: COMPLEX
Details: Complex formed of CYRANO-AGO2-miR-7 in complex with ZSWIM8-ELONGIN B/C, CUL3
Entity ID: #1-#7 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
Buffer solutionpH: 7.8 / Details: 25 mM HEPES, 50 mM NaCl, 1 mM TCEP, pH 7.8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE-PROPANE / Humidity: 95 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 58 e/Å2 / Film or detector model: GATAN K3 BIOCONTINUUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
9PHENIX1.21.1_5286model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 230859 / Symmetry type: POINT

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