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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 / negative regulation of receptor signaling pathway via JAK-STAT / RHOBTB3 ATPase cycle / negative regulation of beige fat cell differentiation / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / negative regulation of mitophagy / cullin-RING ubiquitin ligase complex / regulation of xenophagy / target-directed miRNA degradation ...regulation of cellular response to hypoxia / negative regulation of receptor signaling pathway via JAK-STAT / RHOBTB3 ATPase cycle / negative regulation of beige fat cell differentiation / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / negative regulation of mitophagy / cullin-RING ubiquitin ligase complex / regulation of xenophagy / target-directed miRNA degradation / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / cellular response to chemical stress / Cul7-RING ubiquitin ligase complex / elongin complex / regulation of cell cycle process / neural crest cell differentiation / Replication of the SARS-CoV-1 genome / RNA polymerase II transcription initiation surveillance / positive regulation of protein autoubiquitination / protein neddylation / transcription elongation factor activity / regulation of BMP signaling pathway / NEDD8 ligase activity / regulation of mitophagy / negative regulation of response to oxidative stress / regulation of centrosome duplication / protein K27-linked ubiquitination / VCB complex / Cul5-RING ubiquitin ligase complex / regulation of TOR signaling / ubiquitin-ubiquitin ligase activity / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / SUMOylation of ubiquitinylation proteins / Cul2-RING ubiquitin ligase complex / SCF ubiquitin ligase complex / negative regulation of DNA-templated DNA replication / regulation of mitotic cytokinesis / Cul3-RING ubiquitin ligase complex / regulation of DNA damage checkpoint / negative regulation of transcription elongation by RNA polymerase II / negative regulation of type I interferon production / regulation of miRNA-mediated gene silencing / regulation of natural killer cell activation / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / Prolactin receptor signaling / regulation of cell cycle phase transition / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / regulation of stem cell population maintenance / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / negative regulation of adipose tissue development / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / regulation of cellular response to stress / limb development / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / protein monoubiquitination / negative regulation of signal transduction / cullin family protein binding / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / centrosome duplication / regulation of DNA-templated DNA replication initiation / cell morphogenesis / Formation of HIV elongation complex in the absence of HIV Tat / cilium assembly / ubiquitin-like ligase-substrate adaptor activity / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / intrinsic apoptotic signaling pathway / ribosome-associated ubiquitin-dependent protein catabolic process / signal transduction in response to DNA damage / negative regulation of insulin receptor signaling pathway / negative regulation of TORC1 signaling / Nuclear events stimulated by ALK signaling in cancer / RNA Polymerase II Pre-transcription Events / protein K48-linked ubiquitination / regulation of cellular response to insulin stimulus / positive regulation of TORC1 signaling / transcription-coupled nucleotide-excision repair / post-translational protein modification / negative regulation of autophagy / cellular response to amino acid stimulus / regulation of embryonic development / replication fork processing / transcription corepressor binding / negative regulation of canonical NF-kappaB signal transduction / rescue of stalled cytosolic ribosome / regulation of mitotic cell cycle / Regulation of BACH1 activity / site of DNA damage / protein serine/threonine kinase binding / T cell activation / positive regulation of cell differentiation / TP53 Regulates Transcription of DNA Repair Genes / G1/S transition of mitotic cell cycle / negative regulation of canonical Wnt signaling pathway / transcription initiation at RNA polymerase II promoter
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 / Elongin-C / Elongin B / : / Cullin protein neddylation domain / Cullin, conserved site / Cullin family signature. / Cullin, N-terminal / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / Cullin / Cullin protein neddylation domain / Cullin alpha solenoid 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 / 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
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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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