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- PDB-5n4w: Crystal structure of the Cul2-Rbx1-EloBC-VHL ubiquitin ligase complex -

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Basic information

Entry
Database: PDB / ID: 5n4w
TitleCrystal structure of the Cul2-Rbx1-EloBC-VHL ubiquitin ligase complex
Components
  • Cullin-2CUL2
  • E3 ubiquitin-protein ligase RBX1
  • Elongin-B
  • Elongin-C
  • Von Hippel-Lindau disease tumor suppressor
KeywordsLIGASE / Cullin RING / E3 ubiquitin ligase / VHL / Cullin-2
Function / homology
Function and homology information


regulation of cellular response to hypoxia / cullin-RING-type E3 NEDD8 transferase / cellular response to chemical stress / NEDD8 transferase activity / RHOBTB3 ATPase cycle / cullin-RING ubiquitin ligase complex / negative regulation of receptor signaling pathway via JAK-STAT / transcription elongation factor activity / Cul7-RING ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway ...regulation of cellular response to hypoxia / cullin-RING-type E3 NEDD8 transferase / cellular response to chemical stress / NEDD8 transferase activity / RHOBTB3 ATPase cycle / cullin-RING ubiquitin ligase complex / negative regulation of receptor signaling pathway via JAK-STAT / transcription elongation factor activity / Cul7-RING ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / target-directed miRNA degradation / elongin complex / VCB complex / positive regulation of protein autoubiquitination / protein neddylation / Replication of the SARS-CoV-1 genome / NEDD8 ligase activity / Cul5-RING ubiquitin ligase complex / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / ubiquitin-ubiquitin ligase activity / Cul4A-RING E3 ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / SCF ubiquitin ligase complex / negative regulation of type I interferon production / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / Cul3-RING ubiquitin ligase complex / intracellular non-membrane-bounded organelle / SUMOylation of ubiquitinylation proteins / Prolactin receptor signaling / negative regulation of transcription elongation by RNA polymerase II / protein monoubiquitination / cullin family protein binding / 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 / ubiquitin-like ligase-substrate adaptor activity / protein K48-linked ubiquitination / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / Formation of HIV elongation complex in the absence of HIV Tat / Nuclear events stimulated by ALK signaling in cancer / negative regulation of signal transduction / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / negative regulation of TORC1 signaling / positive regulation of TORC1 signaling / RNA Polymerase II Pre-transcription Events / Regulation of BACH1 activity / T cell activation / post-translational protein modification / intrinsic apoptotic signaling pathway / negative regulation of autophagy / transcription corepressor binding / Degradation of DVL / transcription elongation by RNA polymerase II / Recognition of DNA damage by PCNA-containing replication complex / transcription initiation at RNA polymerase II promoter / positive regulation of cell differentiation / cellular response to amino acid stimulus / TP53 Regulates Transcription of DNA Repair Genes / Degradation of GLI1 by the proteasome / Negative regulation of NOTCH4 signaling / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / 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 / G1/S transition of mitotic cell cycle / negative regulation of canonical Wnt signaling pathway / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / RING-type E3 ubiquitin transferase / Degradation of beta-catenin by the destruction complex / cell morphogenesis / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Inactivation of CSF3 (G-CSF) signaling / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / NOTCH1 Intracellular Domain Regulates Transcription / Formation of TC-NER Pre-Incision Complex / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Formation of Incision Complex in GG-NER / Regulation of expression of SLITs and ROBOs / Interleukin-1 signaling / Dual incision in TC-NER / protein polyubiquitination / Orc1 removal from chromatin / Gap-filling DNA repair synthesis and ligation in TC-NER / Regulation of RAS by GAPs / ubiquitin-protein transferase activity / transcription corepressor activity / positive regulation of protein catabolic process / Regulation of RUNX2 expression and activity / cellular response to UV / ubiquitin protein ligase activity / KEAP1-NFE2L2 pathway
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. / Elongin B / Cullin / Elongin-C / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / Cullin protein neddylation domain / Potassium Channel Kv1.1; Chain A / Potassium Channel Kv1.1; Chain A / 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 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / Zinc finger RING-type profile. / Zinc finger, RING-type / Ubiquitin-like (UB roll) / Ubiquitin family / Ubiquitin homologues / Ubiquitin-like domain / Ubiquitin domain profile. / Ubiquitin-like domain superfamily / Zinc finger, RING/FYVE/PHD-type / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily / Roll / 2-Layer Sandwich / Alpha Beta
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)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.9 Å
AuthorsCardote, T.A.F. / Gadd, M.S. / Ciulli, A.
Funding support United Kingdom, Portugal, 2items
OrganizationGrant numberCountry
European Research CouncilERC-2012-StG-311460 United Kingdom
Fundacao para a Ciencia e TecnologiaSFRH/BD/92417/2013 Portugal
CitationJournal: Structure / Year: 2017
Title: Crystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex.
Authors: Cardote, T.A.F. / Gadd, M.S. / Ciulli, A.
History
DepositionFeb 11, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 7, 2017Provider: repository / Type: Initial release
Revision 1.1Jun 21, 2017Group: Database references / Category: citation
Item: _citation.country / _citation.journal_id_ASTM ..._citation.country / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Oct 24, 2018Group: Advisory / Data collection / Derived calculations
Category: pdbx_validate_close_contact / struct_conn / struct_conn_type
Revision 1.3Apr 24, 2019Group: Data collection / Source and taxonomy / Category: entity_src_gen / Item: _entity_src_gen.pdbx_host_org_cell_line

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cullin-2
V: Von Hippel-Lindau disease tumor suppressor
R: E3 ubiquitin-protein ligase RBX1
B: Elongin-B
C: Elongin-C
hetero molecules


Theoretical massNumber of molelcules
Total (without water)140,3778
Polymers140,1815
Non-polymers1963
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10350 Å2
ΔGint-174 kcal/mol
Surface area56520 Å2
MethodPISA
Unit cell
Length a, b, c (Å)86.038, 190.962, 238.885
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

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Protein , 5 types, 5 molecules AVRBC

#1: Protein Cullin-2 / CUL2 / CUL-2


Mass: 87300.117 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CUL2 / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q13617
#2: Protein Von Hippel-Lindau disease tumor suppressor / Protein G7 / pVHL


Mass: 18558.162 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
#3: Protein E3 ubiquitin-protein ligase RBX1 / Protein ZYP / RING finger protein 75 / RING-box protein 1 / Rbx1 / Regulator of cullins 1


Mass: 11599.248 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RBX1, RNF75, ROC1 / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P62877, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#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 / EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / ...EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / Transcription elongation factor B polypeptide 1


Mass: 10974.616 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15369

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Non-polymers , 1 types, 3 molecules

#6: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Formula: Zn / Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm)

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.51 Å3/Da / Density % sol: 64.92 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.6
Details: 0.1 M Tris pH 7.6, 0.15 M ammonium sulphate, 15% polyethyleneglycol 4000 and 3% 1,4-dioxane or 4% acetonitrile. The sample was crystallised in the presence of a 19-mer peptide mimicking the ...Details: 0.1 M Tris pH 7.6, 0.15 M ammonium sulphate, 15% polyethyleneglycol 4000 and 3% 1,4-dioxane or 4% acetonitrile. The sample was crystallised in the presence of a 19-mer peptide mimicking the substrate HIF-1alpha - residues 559-577 (DEALAPYIPMDDDFQLRSF, with the mutations L559D and M561A and P564 is hydroxyproline).

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.928 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Aug 1, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.928 Å / Relative weight: 1
ReflectionResolution: 3.9→95.481 Å / Num. obs: 34407 / % possible obs: 100 % / Redundancy: 5.7 % / Biso Wilson estimate: 200 Å2 / Rmerge(I) obs: 0.114 / Net I/σ(I): 10.2
Reflection shellResolution: 3.9→4.27 Å / Redundancy: 5.3 % / Rmerge(I) obs: 0.732 / Mean I/σ(I) obs: 2.2 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX(1.11_2558: ???)refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: HOMOLOGY MODEL

Resolution: 3.9→95.48 Å / SU ML: 0.68 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 40.04
RfactorNum. reflection% reflection
Rfree0.346 1802 5.24 %
Rwork0.302 --
obs0.304 34407 99.3 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 191 Å2
Refinement stepCycle: LAST / Resolution: 3.9→95.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7716 0 3 0 7719
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0037855
X-RAY DIFFRACTIONf_angle_d0.69210574
X-RAY DIFFRACTIONf_dihedral_angle_d3.4995127
X-RAY DIFFRACTIONf_chiral_restr0.0431195
X-RAY DIFFRACTIONf_plane_restr0.0041346
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.9001-4.00550.40261350.39732482X-RAY DIFFRACTION99
4.0055-4.12340.37711330.35062509X-RAY DIFFRACTION99
4.1234-4.25650.39821350.3412448X-RAY DIFFRACTION98
4.2565-4.40860.36071420.32152506X-RAY DIFFRACTION100
4.4086-4.58510.34381340.31032568X-RAY DIFFRACTION100
4.5851-4.79380.31491590.30682493X-RAY DIFFRACTION99
4.7938-5.04650.37581620.29742485X-RAY DIFFRACTION100
5.0465-5.36270.32051290.30192513X-RAY DIFFRACTION99
5.3627-5.77670.38841260.33892555X-RAY DIFFRACTION99
5.7767-6.35790.38231390.36542479X-RAY DIFFRACTION99
6.3579-7.27760.39681320.34632534X-RAY DIFFRACTION100
7.2776-9.16780.41641440.29652510X-RAY DIFFRACTION100
9.1678-95.50960.25431320.23782523X-RAY DIFFRACTION99
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.4416-0.9161-0.47042.60240.03270.98591.411-0.8893-0.4805-0.5002-0.44730.04070.58730.24980.78961.0689-0.3334-0.68352.22870.08691.4286-22.33453.0801-61.2783
22.66011.59571.56721.8008-0.72094.46240.51510.497-1.581-0.3201-0.4902-0.62681.9262-0.138-1.90910.8643-0.2563-0.14991.2219-0.44840.38611.7137-6.9799-34.8271
36.60252.29553.06744.31823.57454.01870.58960.07041.01210.5913-0.6006-0.59311.1456-0.2406-0.18751.0145-0.1987-0.04580.69230.21880.697828.4753.989-10.4271
43.38872.36561.20592.7737-0.6651.14650.4383-0.4654-0.52720.7327-0.1995-0.2278-0.42480.0227-0.20871.2817-0.027-0.13240.9750.01451.273944.504934.32778.3282
53.8191.39461.620.65871.09742.3176-0.08450.07870.28-0.5578-0.07920.4548-0.25680.25310.26072.75992.2711-0.04164.91350.58931.7178-27.416636.3384-64.3799
60.2834-0.0082-0.67990.0010.01441.6384-0.3704-0.04630.13890.2860.0839-0.05990.5034-0.04160.19522.93411.2561.66274.1075-0.13284.4692-41.613838.7758-65.2808
71.094-1.15190.11773.9026-0.30471.9341.4182-3.76350.4264-0.54610.7130.01620.6-0.984-2.06221.8979-0.4477-0.21853.72510.40335.7989-38.665528.7954-67.2672
87.8289-6.476-1.9966.85943.82853.62111.35071.57251.1976-1.6292-0.7883-0.97870.0909-0.34110.59413.34082.5002-0.09994.601-0.35951.8977-34.756631.7704-58.7414
95.4695-3.36311.57115.08190.6264.10340.2816-1.00391.13950.1591-0.7327-1.47160.74980.8090.24791.0551-0.2412-0.25911.46930.37761.992160.044245.061612.0342
100.96181.78971.66185.12360.71786.042-1.2555-0.67931.1224-0.4194-1.26110.87050.2689-2.43031.56322.18770.1148-0.35881.794-1.19074.106926.096449.718715.3168
114.6332.81890.85713.52270.6830.15231.1701-0.89761.7102-0.5568-0.0118-0.3669-2.0484-1.7834-0.17512.9877-0.03670.29353.2780.09992.0168-2.366436.4351-85.7069
121.9764-0.80381.49422.66390.9374.2153-0.54571.52251.5369-1.0610.5154-0.2467-2.17530.21480.54641.9334-0.3529-0.3582.64240.65791.0703-15.519627.7148-72.2335
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN 'A' AND (RESID 1 THROUGH 163)
2X-RAY DIFFRACTION2CHAIN 'A' AND (RESID 164 THROUGH 277 )
3X-RAY DIFFRACTION3CHAIN 'A' AND (RESID 278 THROUGH 384 )
4X-RAY DIFFRACTION4CHAIN 'A' AND (RESID 385 THROUGH 745 )
5X-RAY DIFFRACTION5CHAIN 'V' AND (RESID 157 THROUGH 169 )
6X-RAY DIFFRACTION6CHAIN 'V' AND (RESID 170 THROUGH 174 )
7X-RAY DIFFRACTION7CHAIN 'V' AND (RESID 175 THROUGH 184 )
8X-RAY DIFFRACTION8CHAIN 'V' AND (RESID 185 THROUGH 193 )
9X-RAY DIFFRACTION9CHAIN 'R' AND (RESID 17 THROUGH 39 )
10X-RAY DIFFRACTION10CHAIN 'R' AND (RESID 40 THROUGH 102 )
11X-RAY DIFFRACTION11CHAIN 'B' AND (RESID 1 THROUGH 97 )
12X-RAY DIFFRACTION12CHAIN 'C' AND (RESID 17 THROUGH 112 )

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