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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


G2/M DNA replication checkpoint / regulation of cellular response to hypoxia / negative regulation of G2/M transition of mitotic cell cycle / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / cullin-RING ubiquitin ligase complex / cellular response to chemical stress / Cul7-RING ubiquitin ligase complex ...G2/M DNA replication checkpoint / regulation of cellular response to hypoxia / negative regulation of G2/M transition of mitotic cell cycle / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / cullin-RING ubiquitin ligase complex / cellular response to chemical stress / Cul7-RING ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / target-directed miRNA degradation / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / transcription elongation factor activity / VCB complex / elongin complex / Polo-like kinase mediated events / positive regulation of protein autoubiquitination / protein neddylation / Replication of the SARS-CoV-1 genome / NEDD8 ligase activity / negative regulation of response to oxidative stress / Cul5-RING ubiquitin ligase complex / SCF ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / intracellular membraneless organelle / ubiquitin-ubiquitin ligase activity / negative regulation of type I interferon production / Cul4A-RING E3 ubiquitin ligase complex / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / Cul3-RING ubiquitin ligase complex / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / negative regulation of G1/S transition of mitotic cell cycle / SUMOylation of ubiquitinylation proteins / negative regulation of mitophagy / establishment of cell polarity / Prolactin receptor signaling / cullin family protein binding / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / negative regulation of transcription elongation by RNA polymerase II / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / protein monoubiquitination / Tat-mediated elongation of the HIV-1 transcript / ubiquitin-like ligase-substrate adaptor activity / negative regulation of signal transduction / Formation of HIV-1 elongation complex containing HIV-1 Tat / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / Formation of HIV elongation complex in the absence of HIV Tat / Cyclin E associated events during G1/S transition / protein K48-linked ubiquitination / Cyclin A/B1/B2 associated events during G2/M transition / Cyclin A:Cdk2-associated events at S phase entry / RNA Polymerase II Transcription Elongation / Nuclear events stimulated by ALK signaling in cancer / Formation of RNA Pol II elongation complex / Regulation of BACH1 activity / neuron projection morphogenesis / negative regulation of TORC1 signaling / RNA Polymerase II Pre-transcription Events / regulation of cellular response to insulin stimulus / positive regulation of TORC1 signaling / post-translational protein modification / negative regulation of autophagy / intrinsic apoptotic signaling pathway / negative regulation of insulin receptor signaling pathway / protein serine/threonine kinase binding / T cell activation / Degradation of DVL / positive regulation of DNA replication / Recognition of DNA damage by PCNA-containing replication complex / Degradation of GLI1 by the proteasome / transcription corepressor binding / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Negative regulation of NOTCH4 signaling / Vif-mediated degradation of APOBEC3G / Hedgehog 'on' state / DNA Damage Recognition in GG-NER / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / positive regulation of cell differentiation / transcription initiation at RNA polymerase II promoter / cellular response to amino acid stimulus / TP53 Regulates Transcription of DNA Repair Genes / non-membrane spanning protein tyrosine kinase activity / Inactivation of CSF3 (G-CSF) signaling / Degradation of beta-catenin by the destruction complex / transcription elongation by RNA polymerase II / Evasion by RSV of host interferon responses / non-specific protein-tyrosine kinase / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / NOTCH1 Intracellular Domain Regulates Transcription / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / negative regulation of canonical Wnt signaling pathway / G1/S transition of mitotic cell cycle
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 / 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 family / 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

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_37464_half_map_2.map
Projections & Slices
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Histogram

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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