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- EMDB-55480: The Cullin 2 RING VHL E3 ligase dimerised by the homoPROTAC CM11 -

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Basic information

Entry
Database: EMDB / ID: EMD-55480
TitleThe Cullin 2 RING VHL E3 ligase dimerised by the homoPROTAC CM11
Map data
Sample
  • Complex: The ternary complex of the heteropentameric CRL2VHL (VHL-ElonginC-ElonginC-Cul2-Rbx1) dimerized by the homoPROTAC CM11
    • Protein or peptide: Elongin-B
    • Protein or peptide: Elongin-C
    • Protein or peptide: Cullin-2
    • Protein or peptide: E3 ubiquitin-protein ligase RBX1, N-terminally processed
    • Protein or peptide: von Hippel-Lindau disease tumor suppressor
  • Ligand: (2~{S},4~{R})-1-[(2~{S})-2-[2-[2-[2-[2-[2-[2-[2-[[(2~{S})-3,3-dimethyl-1-[(2~{S},4~{R})-2-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylcarbamoyl]-4-oxidanyl-pyrrolidin-1-yl]-1-oxidanylidene-butan-2-yl]amino]-2-oxidanylidene-ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoylamino]-3,3-dimethyl-butanoyl]-~{N}-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-oxidanyl-pyrrolidine-2-carboxamide
KeywordsPROTAC / homoPROTAC / dimerizer / CM11 / VHL / von Hippel-Lindau / Cullin 2 / RING / E3 / ligase / targeted protein degradation
Function / homology
Function and homology information


regulation of cellular response to hypoxia / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / cullin-RING ubiquitin ligase complex / negative regulation of receptor signaling pathway via JAK-STAT / RHOBTB3 ATPase cycle / Cul7-RING ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / cellular response to chemical stress / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling ...regulation of cellular response to hypoxia / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / cullin-RING ubiquitin ligase complex / negative regulation of receptor signaling pathway via JAK-STAT / RHOBTB3 ATPase cycle / Cul7-RING ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / cellular response to chemical stress / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / transcription elongation factor activity / target-directed miRNA degradation / elongin complex / positive regulation of protein autoubiquitination / RNA polymerase II transcription initiation surveillance / protein neddylation / Replication of the SARS-CoV-1 genome / NEDD8 ligase activity / negative regulation of response to oxidative stress / VCB complex / Cul5-RING ubiquitin ligase complex / SCF ubiquitin ligase complex / negative regulation of type I interferon production / ubiquitin-ubiquitin ligase activity / intracellular membraneless organelle / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / Cul2-RING ubiquitin ligase complex / Cul3-RING ubiquitin ligase complex / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / SUMOylation of ubiquitinylation proteins / negative regulation of mitophagy / Prolactin receptor signaling / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / cullin family protein binding / negative regulation of transcription elongation by RNA polymerase II / 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 / protein monoubiquitination / negative regulation of signal transduction / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / ubiquitin-like ligase-substrate adaptor activity / protein K48-linked ubiquitination / Formation of HIV elongation complex in the absence of HIV Tat / Nuclear events stimulated by ALK signaling in cancer / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / negative regulation of TORC1 signaling / transcription-coupled nucleotide-excision repair / RNA Polymerase II Pre-transcription Events / positive regulation of TORC1 signaling / regulation of cellular response to insulin stimulus / negative regulation of insulin receptor signaling pathway / intrinsic apoptotic signaling pathway / protein serine/threonine kinase binding / negative regulation of autophagy / post-translational protein modification / T cell activation / Regulation of BACH1 activity / transcription corepressor binding / TP53 Regulates Transcription of DNA Repair Genes / cellular response to amino acid stimulus / positive regulation of cell differentiation / transcription initiation at RNA polymerase II promoter / Degradation of DVL / transcription elongation by RNA polymerase II / Degradation of GLI1 by the proteasome / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Negative regulation of NOTCH4 signaling / G1/S transition of mitotic cell cycle / Recognition of DNA damage by PCNA-containing replication complex / negative regulation of canonical Wnt signaling pathway / Hedgehog 'on' state / Vif-mediated degradation of APOBEC3G / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / RING-type E3 ubiquitin transferase / Inactivation of CSF3 (G-CSF) signaling / Degradation of beta-catenin by the destruction complex / DNA Damage Recognition in GG-NER / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Evasion by RSV of host interferon responses / NOTCH1 Intracellular Domain Regulates Transcription / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Formation of TC-NER Pre-Incision Complex / Regulation of expression of SLITs and ROBOs / Formation of Incision Complex in GG-NER / Interleukin-1 signaling / cell morphogenesis / protein polyubiquitination / Orc1 removal from chromatin / Regulation of RAS by GAPs
Similarity search - Function
von Hippel-Lindau disease tumour suppressor, beta/alpha domain / von Hippel-Lindau disease tumour suppressor, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / VHL superfamily / von Hippel-Lindau disease tumour suppressor, alpha domain superfamily / von Hippel-Lindau disease tumour suppressor, beta domain superfamily / VHL beta domain / VHL box domain / Zinc finger, RING-H2-type / RING-H2 zinc finger domain ...von Hippel-Lindau disease tumour suppressor, beta/alpha domain / von Hippel-Lindau disease tumour suppressor, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / VHL superfamily / von Hippel-Lindau disease tumour suppressor, alpha domain superfamily / von Hippel-Lindau disease tumour suppressor, beta domain superfamily / VHL beta domain / VHL box domain / Zinc finger, RING-H2-type / RING-H2 zinc finger domain / Cullin protein neddylation domain / : / Cullin, conserved site / Cullin family signature. / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / Cullin / Cullin protein neddylation domain / Elongin-C / Elongin B / Cullin / Cullin, N-terminal / Cullin homology domain / Cullin homology domain superfamily / Cullin alpha solenoid domain / 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 / Zinc finger RING-type profile. / Zinc finger, RING-type / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Zinc finger, RING/FYVE/PHD-type / Ubiquitin-like domain superfamily / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
von Hippel-Lindau disease tumor suppressor / E3 ubiquitin-protein ligase RBX1 / Cullin-2 / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 6.9 Å
AuthorsCrowe C / Ciulli A
Funding supportEuropean Union, United Kingdom, 5 items
OrganizationGrant numberCountry
European Research Council (ERC)ERC-2012-StG-311460 DrugE3CRLsEuropean Union
European Research Council (ERC)875510European Union
Medical Research Council (MRC, United Kingdom)MR/R015791/1 United Kingdom
Wellcome Trust223816/Z/21/Z United Kingdom
Medical Research Council (MRC, United Kingdom)PO 4050845509 United Kingdom
CitationJournal: Biorxiv / Year: 2025
Title: Linker-rigidified VHL homodimerizers convert degraders into stabilizers of non-ubiquitinable ternary complexes
Authors: Crowe C / Salerno A / Sathe G / Marsh G / Maple H / Ciulli A
History
DepositionOct 24, 2025-
Header (metadata) releaseDec 3, 2025-
Map releaseDec 3, 2025-
UpdateDec 3, 2025-
Current statusDec 3, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_55480.png

Downloads & links

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Map

FileDownload / File: emd_55480.map.gz / Format: CCP4 / Size: 824 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 600 pix.
= 444. Å		0.74 Å/pix.
x 600 pix.
= 444. Å		0.74 Å/pix.
x 600 pix.
= 444. 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: 0.0183
Minimum - Maximum-0.039400566 - 0.115613624
Average (Standard dev.)0.00050421513 (±0.0031562021)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions600600600
Spacing600600600
CellA=B=C: 444.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_55480_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_55480_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : The ternary complex of the heteropentameric CRL2VHL (VHL-ElonginC...

EntireName: The ternary complex of the heteropentameric CRL2VHL (VHL-ElonginC-ElonginC-Cul2-Rbx1) dimerized by the homoPROTAC CM11
Components
  • Complex: The ternary complex of the heteropentameric CRL2VHL (VHL-ElonginC-ElonginC-Cul2-Rbx1) dimerized by the homoPROTAC CM11
    • Protein or peptide: Elongin-B
    • Protein or peptide: Elongin-C
    • Protein or peptide: Cullin-2
    • Protein or peptide: E3 ubiquitin-protein ligase RBX1, N-terminally processed
    • Protein or peptide: von Hippel-Lindau disease tumor suppressor
  • Ligand: (2~{S},4~{R})-1-[(2~{S})-2-[2-[2-[2-[2-[2-[2-[2-[[(2~{S})-3,3-dimethyl-1-[(2~{S},4~{R})-2-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylcarbamoyl]-4-oxidanyl-pyrrolidin-1-yl]-1-oxidanylidene-butan-2-yl]amino]-2-oxidanylidene-ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoylamino]-3,3-dimethyl-butanoyl]-~{N}-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-oxidanyl-pyrrolidine-2-carboxamide

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Supramolecule #1: The ternary complex of the heteropentameric CRL2VHL (VHL-ElonginC...

SupramoleculeName: The ternary complex of the heteropentameric CRL2VHL (VHL-ElonginC-ElonginC-Cul2-Rbx1) dimerized by the homoPROTAC CM11
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Elongin-B

MacromoleculeName: Elongin-B / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.619226 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MDVFLMIRRH KTTIFTDAKE SSTVFELKRI VEGILKRPPD EQRLYKDDQL LDDGKTLGEC GFTSQTARPQ APATVGLAFR ADDTFEALC IEPFSSPPEL PDVM

UniProtKB: Elongin-B

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Macromolecule #2: Elongin-C

MacromoleculeName: Elongin-C / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 10.740277 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MYVKLISSDG HEFIVKREHA LTSGTIKAML SGPGQFAENE TNEVNFREIP SHVLSKVCMY FTYKVRYTNS STEIPEFPIA PEIALELLM AANFLD

UniProtKB: Elongin-C

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Macromolecule #3: Cullin-2

MacromoleculeName: Cullin-2 / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 76.636797 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: KPRVVDFDET WNKLLTTIKA VVMLEYVERA TWNDRFSDIY ALCVAYPEPL GERLYTETKI FLENHVRHLH KRVLESEEQV LVMYHRYWE EYSKGADYMD CLYRYLNTQF IKKNKLTEAD LQYGYGGVDM NEPLMEIGEL ALDMWRKLMV EPLQAILIRM L LREIKNDR ...String:
KPRVVDFDET WNKLLTTIKA VVMLEYVERA TWNDRFSDIY ALCVAYPEPL GERLYTETKI FLENHVRHLH KRVLESEEQV LVMYHRYWE EYSKGADYMD CLYRYLNTQF IKKNKLTEAD LQYGYGGVDM NEPLMEIGEL ALDMWRKLMV EPLQAILIRM L LREIKNDR GGEDPNQKVI HGVINSFVHV EQYKKKFPLK FYQEIFESPF LTETGEYYKQ EASNLLQESN CSQYMEKVLG RL KDEEIRC RKYLHPSSYT KVIHECQQRM VADHLQFLHA ECHNIIRQEK KNDMANMYVL LRAVSTGLPH MIQELQNHIH DEG LRATSN LTQENMPTLF VESVLEVHGK FVQLINTVLN GDQHFMSALD KALTSVVNYR EPKSVCKAPE LLAKYCDNLL KKSA KGMTE NEVEDRLTSF ITVFKYIDDK DVFQKFYARM LAKRLIHGLS MSMDSEEAMI NKLKQACGYE FTSKLHRMYT DMSVS ADLN NKFNNFIKNQ DTVIDLGISF QIYVLQAGAW PLTQAPSSTF AIPQELEKSV QMFELFYSQH FSGRKLTWLH YLCTGE VKM NYLGKPYVAM VTTYQMAVLL AFNNSETVSY KELQDSTQMN EKELTKTIKS LLDVKMINHD SEKEDIDAES SFSLNMN FS SKRTKFKITT SMQ

UniProtKB: Cullin-2

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Macromolecule #4: E3 ubiquitin-protein ligase RBX1, N-terminally processed

MacromoleculeName: E3 ubiquitin-protein ligase RBX1, N-terminally processed
type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 10.526048 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
KRFEVKKWNA VALWAWDIVV DNCAICRNHI MDLCIECQAN QASATSEECT VAWGVCNHAF HFHCISRWLK TRQVCPLDNR EWEFQKYGH

UniProtKB: E3 ubiquitin-protein ligase RBX1

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Macromolecule #5: von Hippel-Lindau disease tumor suppressor

MacromoleculeName: von Hippel-Lindau disease tumor suppressor / type: protein_or_peptide / ID: 5 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 16.33562 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
VLRSVNSREP SQVIFCNRSP RVVLPVWLNF DGEPQPYPTL PPGTGRRIHS YRGHLWLFRD AGTHDGLLVN QTELFVPSLN VDGQPIFAN ITLPVYTLKE RCLQVVRSLV KPENYRRLDI VRSLYEDLED HPNVQKDLER LT

UniProtKB: von Hippel-Lindau disease tumor suppressor

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Macromolecule #6: (2~{S},4~{R})-1-[(2~{S})-2-[2-[2-[2-[2-[2-[2-[2-[[(2~{S})-3,3-dim...

MacromoleculeName: (2~{S},4~{R})-1-[(2~{S})-2-[2-[2-[2-[2-[2-[2-[2-[[(2~{S})-3,3-dimethyl-1-[(2~{S},4~{R})-2-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylcarbamoyl]-4-oxidanyl-pyrrolidin-1-yl]-1-oxidanylidene- ...Name: (2~{S},4~{R})-1-[(2~{S})-2-[2-[2-[2-[2-[2-[2-[2-[[(2~{S})-3,3-dimethyl-1-[(2~{S},4~{R})-2-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylcarbamoyl]-4-oxidanyl-pyrrolidin-1-yl]-1-oxidanylidene-butan-2-yl]amino]-2-oxidanylidene-ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoylamino]-3,3-dimethyl-butanoyl]-~{N}-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-oxidanyl-pyrrolidine-2-carboxamide
type: ligand / ID: 6 / Number of copies: 1 / Formula: A1JTC
Molecular weightTheoretical: 1.179447 KDa

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation state3D array

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 57.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.2 µm / Nominal defocus min: 1.7 µm

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

8rwz

Final reconstructionResolution.type: BY AUTHOR / Resolution: 6.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 68789
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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