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- PDB-8bdm: VCB in complex with compound 26 -

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Basic information

Entry
Database: PDB / ID: 8bdm
TitleVCB in complex with compound 26
Components
  • Elongin-B
  • Elongin-C
  • von Hippel-Lindau disease tumor suppressor
KeywordsLIGASE / PROTAC / degrader / complex / E3 ligase / VHL / VCB / VH032
Function / homology
Function and homology information


regulation of cellular response to hypoxia / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / transcription elongation factor activity / target-directed miRNA degradation / VCB complex / elongin complex / Replication of the SARS-CoV-1 genome / Cul5-RING ubiquitin ligase complex / intracellular membraneless organelle ...regulation of cellular response to hypoxia / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / transcription elongation factor activity / target-directed miRNA degradation / VCB complex / elongin complex / Replication of the SARS-CoV-1 genome / Cul5-RING ubiquitin ligase complex / intracellular membraneless organelle / Cul2-RING ubiquitin ligase complex / SUMOylation of ubiquitinylation proteins / negative regulation of transcription elongation by RNA polymerase II / 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 / Tat-mediated elongation of the HIV-1 transcript / ubiquitin-like ligase-substrate adaptor activity / Formation of HIV-1 elongation complex containing HIV-1 Tat / negative regulation of signal transduction / Formation of HIV elongation complex in the absence of HIV Tat / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / negative regulation of TORC1 signaling / RNA Polymerase II Pre-transcription Events / negative regulation of autophagy / transcription corepressor binding / positive regulation of cell differentiation / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / transcription elongation by RNA polymerase II / Vif-mediated degradation of APOBEC3G / Inactivation of CSF3 (G-CSF) signaling / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / cell morphogenesis / Evasion by RSV of host interferon responses / Regulation of expression of SLITs and ROBOs / ubiquitin-protein transferase activity / transcription corepressor activity / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Neddylation / Replication of the SARS-CoV-2 genome / regulation of gene expression / ubiquitin-dependent protein catabolic process / protein-containing complex assembly / protein-macromolecule adaptor activity / DNA-binding transcription factor binding / molecular adaptor activity / cellular response to hypoxia / proteasome-mediated ubiquitin-dependent protein catabolic process / amyloid fibril formation / protein stabilization / protein ubiquitination / negative regulation of cell population proliferation / negative regulation of gene expression / ubiquitin protein ligase binding / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / enzyme binding / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / mitochondrion / proteolysis / nucleoplasm / nucleus / plasma membrane / cytosol
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 / Elongin-C / Elongin B ...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 / Elongin-C / Elongin B / Potassium Channel Kv1.1; Chain A / Potassium Channel Kv1.1; Chain A / 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 / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-QE9 / von Hippel-Lindau disease tumor suppressor / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.021 Å
AuthorsSorrell, F.J. / Mueller, J.E. / Lehmann, M. / Wegener, A.
Funding support Germany, 1items
OrganizationGrant numberCountry
Not funded Germany
CitationJournal: Chemmedchem / Year: 2023
Title: Systematic Potency and Property Assessment of VHL Ligands and Implications on PROTAC Design.
Authors: Krieger, J. / Sorrell, F.J. / Wegener, A.A. / Leuthner, B. / Machrouhi-Porcher, F. / Hecht, M. / Leibrock, E.M. / Muller, J.E. / Eisert, J. / Hartung, I.V. / Schlesiger, S.
History
DepositionOct 19, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 15, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 22, 2023Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Apr 26, 2023Group: Database references / Category: citation / Item: _citation.journal_volume
Revision 1.3Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.4Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _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
G: Elongin-B
H: Elongin-C
I: von Hippel-Lindau disease tumor suppressor
D: Elongin-B
E: Elongin-C
F: von Hippel-Lindau disease tumor suppressor
A: Elongin-B
B: Elongin-C
C: von Hippel-Lindau disease tumor suppressor
J: Elongin-B
K: Elongin-C
L: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)168,76016
Polymers166,53312
Non-polymers2,2274
Water13,854769
1
G: Elongin-B
H: Elongin-C
I: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,1904
Polymers41,6333
Non-polymers5571
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4690 Å2
ΔGint-39 kcal/mol
Surface area16430 Å2
MethodPISA
2
D: Elongin-B
E: Elongin-C
F: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,1904
Polymers41,6333
Non-polymers5571
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4520 Å2
ΔGint-38 kcal/mol
Surface area16440 Å2
MethodPISA
3
A: Elongin-B
B: Elongin-C
C: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,1904
Polymers41,6333
Non-polymers5571
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4600 Å2
ΔGint-38 kcal/mol
Surface area16660 Å2
MethodPISA
4
J: Elongin-B
K: Elongin-C
L: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,1904
Polymers41,6333
Non-polymers5571
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4630 Å2
ΔGint-37 kcal/mol
Surface area16720 Å2
MethodPISA
Unit cell
Length a, b, c (Å)92.894, 92.894, 364.016
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number91
Space group name H-MP4122

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Components

#1: 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: 11852.389 Da / Num. of mol.: 4
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
#2: 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.: 4
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
#3: Protein
von Hippel-Lindau disease tumor suppressor / Protein G7 / pVHL


Mass: 18806.273 Da / Num. of mol.: 4
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: Chemical
ChemComp-QE9 / (2~{S},4~{R})-~{N}-[[2-(2-methoxyethoxy)-4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1-[(2~{R})-3-methyl-2-(3-methyl-1,2-oxazol-5-yl)butanoyl]-4-oxidanyl-pyrrolidine-2-carboxamide


Mass: 556.674 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C28H36N4O6S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 769 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.37 Å3/Da / Density % sol: 48.09 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 10-20% PEG 8000, 0.2 M magnesium acetate and 0.1 M sodium cacodylate pH 6.5, soaked with 1mM compound

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99971 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 23, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99971 Å / Relative weight: 1
ReflectionResolution: 2.02→90.17 Å / Num. obs: 100347 / % possible obs: 95 % / Redundancy: 13.1 % / Biso Wilson estimate: 47.57 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.095 / Rpim(I) all: 0.027 / Rrim(I) all: 0.099 / Net I/σ(I): 14.8
Reflection shellResolution: 2.021→2.027 Å / Redundancy: 14.1 % / Rmerge(I) obs: 3.824 / Num. unique obs: 1007 / CC1/2: 0.361 / Rpim(I) all: 1.052 / Rrim(I) all: 3.967 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
BUSTER2.Xrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5nw1

5nw1


Resolution: 2.021→82.74 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.947 / SU R Cruickshank DPI: 0.224 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.236 / SU Rfree Blow DPI: 0.187 / SU Rfree Cruickshank DPI: 0.184
RfactorNum. reflection% reflectionSelection details
Rfree0.2554 4885 5.05 %RANDOM
Rwork0.2245 ---
obs0.2261 96693 91.6 %-
Displacement parametersBiso mean: 59.39 Å2
Baniso -1Baniso -2Baniso -3
1--1.7014 Å20 Å20 Å2
2---1.7014 Å20 Å2
3---3.4028 Å2
Refine analyzeLuzzati coordinate error obs: 0.32 Å
Refinement stepCycle: LAST / Resolution: 2.021→82.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10602 0 228 769 11599
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00811107HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9615111HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3808SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1860HARMONIC5
X-RAY DIFFRACTIONt_it11107HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.44
X-RAY DIFFRACTIONt_other_torsion17.63
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1463SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact9303SEMIHARMONIC4
LS refinement shellResolution: 2.021→2.04 Å
RfactorNum. reflection% reflection
Rfree0.3834 103 5.33 %
Rwork0.3832 1831 -
obs--66.6 %
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)
13.1554-1.5548-1.92851.39413.08545.8716-0.0229-0.28510.22950.53720.01190.05180.9553-0.1190.01090.1638-0.1061-0.00150.03990.0267-0.238628.8902-1.50843.4851
21.29990.1741-0.90952.72561.86255.39970.0210.01020.02250.3642-0.05560.00690.6171-0.26190.03460.14-0.0548-0.0259-0.05780.0161-0.16131.9966-5.8326.0579
31.114-0.94070.68784.8027-1.33811.47490.08570.0233-0.0238-0.0627-0.0283-0.0611-0.10360.0402-0.05740.0315-0.03750.0727-0.0395-0.0518-0.099338.869515.27068.6223
43.1945-1.6614-1.90961.34011.69813.3978-0.0661-0.3144-0.02240.1979-0.0066-0.05660.17790.1750.0727-0.0121-0.01750.03560.00640.0325-0.081974.93522.469743.3634
51.33470.2575-0.79372.59060.19013.7179-0.0716-0.0177-0.106-0.2002-0.03420.0493-0.0124-0.04890.10590.02550.00580.0439-0.0774-0.0102-0.050678.2507-1.489925.8815
60.7801-0.58990.58454.6272-2.66141.84590.01610.058-0.0423-0.01780.01380.1456-0.07830.0785-0.030.1038-0.03180.1316-0.099-0.0364-0.093285.30919.8048.3335
72.0072-1.0112-1.74541.42390.73944.9578-0.1203-0.10540.13720.1754-0.01280.03030.2165-0.31810.13310.0713-0.0180.0376-0.0080.0167-0.149933.442343.720243.5062
80.64540.3435-0.45293.5731-0.57942.6971-0.00740.05450.0219-0.4381-0.05210.25540.2486-0.23920.05950.20440.0002-0.0124-0.07750.0306-0.122835.112140.582126.0018
90.9432-0.81070.49172.3572-1.23211.0991-0.0238-0.00320.0151-0.2523-0.07140.03350.2803-0.03580.09520.25190.01210.0155-0.0856-0.0045-0.118138.733261.67517.7832
101.7932-1.29210.02412.1206-1.13863.2749-0.03710.0375-0.0367-0.1928-0.05480.11910.00490.15830.0919-0.0128-0.04230.00480.04950.0539-0.106245.073113.921747.9184
112.82670.5543-0.50990.8348-0.53652.8495-0.1026-0.42790.0676-0.0245-0.01590.0565-0.1620.41870.1185-0.1008-0.01120.01770.21590.0539-0.134747.816412.125365.378
122.0934-0.4823-0.95380.9889-0.43452.16-0.0531-0.24640.0786-0.0593-0.08670.0302-0.0630.25070.1397-0.13080.0071-0.00440.17560.0757-0.083926.73527.696783.1801
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }
3X-RAY DIFFRACTION3{ C|* }
4X-RAY DIFFRACTION4{ D|* }
5X-RAY DIFFRACTION5{ E|* }
6X-RAY DIFFRACTION6{ F|* }
7X-RAY DIFFRACTION7{ G|* }
8X-RAY DIFFRACTION8{ H|* }
9X-RAY DIFFRACTION9{ I|* }
10X-RAY DIFFRACTION10{ J|* }
11X-RAY DIFFRACTION11{ K|* }
12X-RAY DIFFRACTION12{ L|* }

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