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- EMDB-37464: The complex structure of Cul2-VCB-Protac-Wee1 -

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Entry
Database: EMDB / ID: EMD-37464
TitleThe complex structure of Cul2-VCB-Protac-Wee1
Map data
Sample
  • Complex: Holo E3 complex including Cullin2, RBX1, VHL, ElongingB and ElonginC bound with Wee1 mediated by protac
    • 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
    • Protein or peptide: Elongin-B
    • Protein or peptide: Elongin-C
    • Protein or peptide: Wee1-like protein kinase
  • Ligand: (2S,4R)-1-[(2S)-3,3-dimethyl-2-[3-[4-[4-[4-[[3-oxidanylidene-1-[6-(2-oxidanylpropan-2-yl)pyridin-2-yl]-2-prop-2-enyl-pyrazolo[3,4-d]pyrimidin-6-yl]amino]phenyl]piperazin-1-yl]butoxy]propanoylamino]butanoyl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-oxidanyl-pyrrolidine-2-carboxamide
KeywordsE3 ligase complex / LIGASE
Function / homology
Function and homology information


negative regulation of G2/M transition of mitotic cell cycle / regulation of cellular response to hypoxia / G2/M DNA replication checkpoint / 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 / cullin-RING ubiquitin ligase complex / negative regulation of mitophagy ...negative regulation of G2/M transition of mitotic cell cycle / regulation of cellular response to hypoxia / G2/M DNA replication checkpoint / 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 / cullin-RING ubiquitin ligase complex / negative regulation of mitophagy / regulation of xenophagy / target-directed miRNA degradation / Polo-like kinase mediated events / cellular response to chemical stress / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / elongin complex / Cul7-RING ubiquitin ligase complex / VCB complex / regulation of cell cycle process / Replication of the SARS-CoV-1 genome / neural crest cell differentiation / 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 / negative regulation of G1/S transition of mitotic cell cycle / regulation of mitophagy / negative regulation of response to oxidative stress / regulation of centrosome duplication / protein K27-linked ubiquitination / positive regulation of cilium assembly / Cul5-RING ubiquitin ligase complex / ubiquitin-ubiquitin ligase activity / regulation of TOR signaling / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / SUMOylation of ubiquitinylation proteins / Cul2-RING ubiquitin ligase complex / negative regulation of DNA-templated DNA replication / SCF ubiquitin ligase complex / regulation of DNA damage checkpoint / regulation of mitotic cytokinesis / negative regulation of transcription elongation by RNA polymerase II / negative regulation of type I interferon production / Cul3-RING ubiquitin ligase complex / regulation of miRNA-mediated gene silencing / regulation of natural killer cell activation / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / Prolactin receptor signaling / nucleotide-excision repair complex / regulation of cell cycle phase transition / Cul4-RING E3 ubiquitin ligase complex / regulation of stem cell population maintenance / Cul4A-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / negative regulation of adipose tissue development / Cul4B-RING E3 ubiquitin ligase complex / 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 / negative regulation of signal transduction / protein monoubiquitination / cullin family protein binding / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / Cyclin E associated events during G1/S transition / centrosome duplication / cell morphogenesis / regulation of DNA-templated DNA replication initiation / Formation of HIV elongation complex in the absence of HIV Tat / Cyclin A:Cdk2-associated events at S phase entry / cilium assembly / Cyclin A/B1/B2 associated events during G2/M transition / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / RNA Polymerase II Transcription Elongation / ubiquitin-like ligase-substrate adaptor activity / 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 / protein K63-linked ubiquitination / RNA Polymerase II Pre-transcription Events / Nuclear events stimulated by ALK signaling in cancer / regulation of cellular response to insulin stimulus / protein K48-linked ubiquitination / transcription-coupled nucleotide-excision repair / post-translational protein modification / positive regulation of TORC1 signaling / negative regulation of TORC1 signaling / regulation of embryonic development / negative regulation of autophagy / positive regulation of DNA replication / replication fork processing / cellular response to amino acid stimulus / transcription corepressor binding
Similarity search - Function
Wee1-like protein kinase / : / 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 ...Wee1-like protein kinase / : / 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 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Winged helix-like DNA-binding domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Wee1-like protein kinase / 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: 3.64 Å
AuthorsWang P / Zhang TT
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: Structure of Cul2-VCB-Protac-Wee1 complex at 3.6 Angstrom resolution.
Authors: Wang P / Zhang TT
History
DepositionSep 15, 2023-
Header (metadata) releaseSep 18, 2024-
Map releaseSep 18, 2024-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_37464.png

Downloads & links

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Map

FileDownload / File: emd_37464.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 480 pix.
= 406.08 Å		0.85 Å/pix.
x 480 pix.
= 406.08 Å		0.85 Å/pix.
x 480 pix.
= 406.08 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.846 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.075
Minimum - Maximum-0.20215753 - 0.51668423
Average (Standard dev.)0.00013763286 (±0.007705573)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions480480480
Spacing480480480
CellA=B=C: 406.08002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_37464_half_map_1.map
Projections & Slices
AxesZYX

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Density Histograms

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Histogram (log scale)

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Half map: #1

Fileemd_37464_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Holo E3 complex including Cullin2, RBX1, VHL, ElongingB and Elong...

EntireName: Holo E3 complex including Cullin2, RBX1, VHL, ElongingB and ElonginC bound with Wee1 mediated by protac
Components
  • Complex: Holo E3 complex including Cullin2, RBX1, VHL, ElongingB and ElonginC bound with Wee1 mediated by protac
    • 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
    • Protein or peptide: Elongin-B
    • Protein or peptide: Elongin-C
    • Protein or peptide: Wee1-like protein kinase
  • Ligand: (2S,4R)-1-[(2S)-3,3-dimethyl-2-[3-[4-[4-[4-[[3-oxidanylidene-1-[6-(2-oxidanylpropan-2-yl)pyridin-2-yl]-2-prop-2-enyl-pyrazolo[3,4-d]pyrimidin-6-yl]amino]phenyl]piperazin-1-yl]butoxy]propanoylamino]butanoyl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-oxidanyl-pyrrolidine-2-carboxamide

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Supramolecule #1: Holo E3 complex including Cullin2, RBX1, VHL, ElongingB and Elong...

SupramoleculeName: Holo E3 complex including Cullin2, RBX1, VHL, ElongingB and ElonginC bound with Wee1 mediated by protac
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#6
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Cullin-2

MacromoleculeName: Cullin-2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 87.09893 KDa
Recombinant expressionOrganism: Insect cell expression vector pTIE1 (others)
SequenceString: MSLKPRVVDF DETWNKLLTT IKAVVMLEYV ERATWNDRFS DIYALCVAYP EPLGERLYTE TKIFLENHVR HLHKRVLESE EQVLVMYHR YWEEYSKGAD YMDCLYRYLN TQFIKKNKLT EADLQYGYGG VDMNEPLMEI GELALDMWRK LMVEPLQAIL I RMLLREIK ...String:
MSLKPRVVDF DETWNKLLTT IKAVVMLEYV ERATWNDRFS DIYALCVAYP EPLGERLYTE TKIFLENHVR HLHKRVLESE EQVLVMYHR YWEEYSKGAD YMDCLYRYLN TQFIKKNKLT EADLQYGYGG VDMNEPLMEI GELALDMWRK LMVEPLQAIL I RMLLREIK NDRGGEDPNQ KVIHGVINSF VHVEQYKKKF PLKFYQEIFE SPFLTETGEY YKQEASNLLQ ESNCSQYMEK VL GRLKDEE IRCRKYLHPS SYTKVIHECQ QRMVADHLQF LHAECHNIIR QEKKNDMANM YVLLRAVSTG LPHMIQELQN HIH DEGLRA TSNLTQENMP TLFVESVLEV HGKFVQLINT VLNGDQHFMS ALDKALTSVV NYREPKSVCK APELLAKYCD NLLK KSAKG MTENEVEDRL TSFITVFKYI DDKDVFQKFY ARMLAKRLIH GLSMSMDSEE AMINKLKQAC GYEFTSKLHR MYTDM SVSA DLNNKFNNFI KNQDTVIDLG ISFQIYVLQA GAWPLTQAPS STFAIPQELE KSVQMFELFY SQHFSGRKLT WLHYLC TGE VKMNYLGKPY VAMVTTYQMA VLLAFNNSET VSYKELQDST QMNEKELTKT IKSLLDVKMI NHDSEKEDID AESSFSL NM NFSSKRTKFK ITTSMQKDTP QEMEQTRSAV DEDRKMYLQA AIVRIMKARK VLRHNALIQE VISQSRARFN PSISMIKK C IEVLIDKQYI ERSQASADEY SYVA

UniProtKB: Cullin-2

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Macromolecule #2: E3 ubiquitin-protein ligase RBX1, N-terminally processed

MacromoleculeName: E3 ubiquitin-protein ligase RBX1, N-terminally processed
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 9.634012 KDa
Recombinant expressionOrganism: Insect cell expression vector pTIE1 (others)
SequenceString:
RFEVKKWNAV ALWAWDIVVD NCAICRNHIM DLCIECQANQ ASATSEECTV AWGVCNHAFH FHCISRWLKT RQVCPLDNRE WE

UniProtKB: E3 ubiquitin-protein ligase RBX1

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Macromolecule #3: von Hippel-Lindau disease tumor suppressor

MacromoleculeName: von Hippel-Lindau disease tumor suppressor / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 18.012527 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
PRPVLRSVNS REPSQVIFCN RSPRVVLPVW LNFDGEPQPY PTLPPGTGRR IHSYRGHLWL FRDAGTHDGL LVNQTELFVP SLNVDGQPI FANITLPVYT LKERCLQVVR SLVKPENYRR LDIVRSLYED LEDHPNVQKD LERLTQERIA HQRMGD

UniProtKB: von Hippel-Lindau disease tumor suppressor

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Macromolecule #4: Elongin-B

MacromoleculeName: Elongin-B / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.748406 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MDVFLMIRRH KTTIFTDAKE SSTVFELKRI VEGILKRPPD EQRLYKDDQL LDDGKTLGEC GFTSQTARPQ APATVGLAFR ADDTFEALC IEPFSSPPEL PDVMK

UniProtKB: Elongin-B

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Macromolecule #5: Elongin-C

MacromoleculeName: Elongin-C / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 10.84342 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MYVKLISSDG HEFIVKREHA LTSGTIKAML SGPGQFAENE TNEVNFREIP SHVLSKVCMY FTYKVRYTNS STEIPEFPIA PEIALELLM AANFLDC

UniProtKB: Elongin-C

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Macromolecule #6: Wee1-like protein kinase

MacromoleculeName: Wee1-like protein kinase / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 32.225691 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: GMKSRYTTEF HELEKIGSGE FGSVFKCVKR LDGCIYAIKR SKKPLAGSVD EQNALREVYA HAVLGQHSHV VRYFSAWAED DHMLIQNEY CNGGSLADAI SENYRIMSYF KEAELKDLLL QVGRGLRYIH SMSLVHMDIK PSNIFISRTS IPNAASEEGD E DDWASNKV ...String:
GMKSRYTTEF HELEKIGSGE FGSVFKCVKR LDGCIYAIKR SKKPLAGSVD EQNALREVYA HAVLGQHSHV VRYFSAWAED DHMLIQNEY CNGGSLADAI SENYRIMSYF KEAELKDLLL QVGRGLRYIH SMSLVHMDIK PSNIFISRTS IPNAASEEGD E DDWASNKV MFKIGDLGHV TRISSPQVEE GDSRFLANEV LQENYTHLPK ADIFALALTV VCAAGAEPLP RNGDQWHEIR QG RLPRIPQ VLSQEFTELL KVMIHPDPER RPSAMALVKH SVLLSASRK

UniProtKB: Wee1-like protein kinase

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Macromolecule #7: (2S,4R)-1-[(2S)-3,3-dimethyl-2-[3-[4-[4-[4-[[3-oxidanylidene-1-[6...

MacromoleculeName: (2S,4R)-1-[(2S)-3,3-dimethyl-2-[3-[4-[4-[4-[[3-oxidanylidene-1-[6-(2-oxidanylpropan-2-yl)pyridin-2-yl]-2-prop-2-enyl-pyrazolo[3,4-d]pyrimidin-6-yl]amino]phenyl]piperazin-1-yl]butoxy] ...Name: (2S,4R)-1-[(2S)-3,3-dimethyl-2-[3-[4-[4-[4-[[3-oxidanylidene-1-[6-(2-oxidanylpropan-2-yl)pyridin-2-yl]-2-prop-2-enyl-pyrazolo[3,4-d]pyrimidin-6-yl]amino]phenyl]piperazin-1-yl]butoxy]propanoylamino]butanoyl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-oxidanyl-pyrrolidine-2-carboxamide
type: ligand / ID: 7 / Number of copies: 1 / Formula: W6U
Molecular weightTheoretical: 1.043285 KDa

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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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 1.275 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 0.31 µm / Nominal defocus min: 0.15 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

5n4w

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.64 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 312419
Initial angle assignmentType: MAXIMUM LIKELIHOOD

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