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- PDB-8wdk: The complex structure of Cul2-VCB-Protac-Wee1 -

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Basic information

Entry
Database: PDB / ID: 8wdk
TitleThe complex structure of Cul2-VCB-Protac-Wee1
Components
  • Cullin-2
  • E3 ubiquitin-protein ligase RBX1, N-terminally processed
  • Elongin-B
  • Elongin-C
  • Wee1-like protein kinase
  • von Hippel-Lindau disease tumor suppressor
KeywordsLIGASE / E3 ligase complex
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 / Cul7-RING ubiquitin ligase complex / elongin 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 / negative regulation of transcription elongation by RNA polymerase II / regulation of mitotic cytokinesis / negative regulation of type I interferon production / Cul3-RING ubiquitin ligase complex / regulation of miRNA-mediated gene silencing / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / regulation of natural killer cell activation / Prolactin receptor signaling / nucleotide-excision repair complex / Cul4-RING E3 ubiquitin ligase complex / regulation of cell cycle phase transition / regulation of stem cell population maintenance / 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 / Cul4B-RING E3 ubiquitin ligase complex / regulation of cellular response to stress / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / limb development / Cul4A-RING E3 ubiquitin ligase complex / 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 / Formation of HIV elongation complex in the absence of HIV Tat / Cyclin A:Cdk2-associated events at S phase entry / regulation of DNA-templated DNA replication initiation / 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 / negative regulation of insulin receptor signaling pathway / signal transduction in response to DNA damage / protein K63-linked ubiquitination / Nuclear events stimulated by ALK signaling in cancer / RNA Polymerase II Pre-transcription Events / regulation of cellular response to insulin stimulus / protein K48-linked ubiquitination / post-translational protein modification / positive regulation of TORC1 signaling / transcription-coupled nucleotide-excision repair / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.64 Å
AuthorsWang, P. / Zhang, T.T.
Funding support1items
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, T.T.
History
DepositionSep 15, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 18, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 16, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cullin-2
R: E3 ubiquitin-protein ligase RBX1, N-terminally processed
V: von Hippel-Lindau disease tumor suppressor
B: Elongin-B
C: Elongin-C
W: Wee1-like protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)170,6067
Polymers169,5636
Non-polymers1,0431
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 , 6 types, 6 molecules ARVBCW

#1: Protein Cullin-2


Mass: 87098.930 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CUL2
Production host: Insect cell expression vector pTIE1 (others)
References: UniProt: Q13617
#2: Protein E3 ubiquitin-protein ligase RBX1, N-terminally processed / E3 ubiquitin-protein transferase RBX1 / N-terminally processed


Mass: 9634.012 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RBX1
Production host: Insect cell expression vector pTIE1 (others)
References: UniProt: P62877
#3: Protein von Hippel-Lindau disease tumor suppressor


Mass: 18012.527 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VHL / Production host: Escherichia coli (E. coli) / References: UniProt: P40337
#4: 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: 11748.406 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOB, TCEB2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15370
#5: Protein Elongin-C


Mass: 10843.420 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC / Production host: Escherichia coli (E. coli) / References: UniProt: Q15369
#6: Protein Wee1-like protein kinase


Mass: 32225.691 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WEE1 / Production host: Escherichia coli (E. coli) / References: UniProt: P30291

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Non-polymers , 1 types, 1 molecules

#7: Chemical ChemComp-W6U / (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


Mass: 1043.285 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C55H70N12O7S / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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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: Holo E3 complex including Cullin2, RBX1, VHL, ElongingB and ElonginC bound with Wee1 mediated by protac
Type: COMPLEX / Entity ID: #1-#6 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 310 nm / Nominal defocus min: 150 nm
Image recordingElectron dose: 1.275 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.64 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 312419 / Symmetry type: POINT

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