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- PDB-8bdt: Ternary complex between VCB, BRD4-BD2 and PROTAC 51 -

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Basic information

Entry
Database: PDB / ID: 8bdt
TitleTernary complex between VCB, BRD4-BD2 and PROTAC 51
Components
  • Bromodomain-containing protein 4
  • Elongin-B
  • Elongin-C
  • von Hippel-Lindau disease tumor suppressor
KeywordsLIGASE / PROTAC / VHL / VCB / Complex / Ternary complex / Degrader / E3 Ligase
Function / homology
Function and homology information


regulation of cellular response to hypoxia / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / target-directed miRNA degradation / transcription elongation factor activity / 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 / target-directed miRNA degradation / transcription elongation factor activity / 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 / RNA polymerase II C-terminal domain binding / P-TEFb complex binding / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / negative regulation of DNA damage checkpoint / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / negative regulation by host of viral transcription / 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 / positive regulation of T-helper 17 cell lineage commitment / 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 / protein serine/threonine kinase binding / positive regulation of G2/M transition of mitotic cell cycle / RNA Polymerase II Pre-transcription Events / RNA polymerase II CTD heptapeptide repeat kinase activity / negative regulation of autophagy / condensed nuclear chromosome / transcription corepressor binding / histone reader activity / : / positive regulation of transcription elongation by RNA polymerase II / positive regulation of cell differentiation / transcription coregulator activity / 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 / cell morphogenesis / Evasion by RSV of host interferon responses / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Regulation of expression of SLITs and ROBOs / ubiquitin-protein transferase activity / transcription corepressor activity / p53 binding / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Neddylation / chromosome / microtubule cytoskeleton / regulation of gene expression / Replication of the SARS-CoV-2 genome / protein-containing complex assembly / ubiquitin-dependent protein catabolic process / regulation of inflammatory response / protein-macromolecule adaptor activity / DNA-binding transcription factor binding / molecular adaptor activity / cellular response to hypoxia / histone binding / amyloid fibril formation / proteasome-mediated ubiquitin-dependent protein catabolic process / Potential therapeutics for SARS / positive regulation of canonical NF-kappaB signal transduction / transcription coactivator activity / transcription cis-regulatory region binding / protein stabilization / protein ubiquitination / cilium / chromatin remodeling / negative regulation of cell population proliferation / negative regulation of gene expression / protein serine/threonine kinase activity / ubiquitin protein ligase binding / DNA damage response / chromatin binding / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / chromatin / positive regulation of DNA-templated transcription / enzyme binding / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / positive regulation of transcription by RNA polymerase II / 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 / Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / SKP1/BTB/POZ domain superfamily / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / Bromodomain, conserved site / Bromodomain signature. / Ubiquitin-like (UB roll) / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily / Roll / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
MALONATE ION / Chem-QLX / Bromodomain-containing protein 4 / von Hippel-Lindau disease tumor suppressor / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsSorrell, F.J. / Mueller, J.E. / Lehmann, M. / Wegener, A.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 20, 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 ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
B: Elongin-B
C: Elongin-C
D: von Hippel-Lindau disease tumor suppressor
E: Bromodomain-containing protein 4
F: Elongin-B
G: Elongin-C
H: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,94611
Polymers112,6498
Non-polymers2,2983
Water1,18966
1
A: Bromodomain-containing protein 4
B: Elongin-B
C: Elongin-C
D: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,4225
Polymers56,3244
Non-polymers1,0981
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
E: Bromodomain-containing protein 4
F: Elongin-B
G: Elongin-C
H: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,5246
Polymers56,3244
Non-polymers1,2002
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)82.483, 82.483, 169.088
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number145
Space group name H-MP32
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21E
12B
22F
13C
23G
14D
24H

NCS domain segments:

Component-ID: _ / Refine code: _

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11SERSERMETMETAA351 - 45720 - 126
21SERSERMETMETEE351 - 45720 - 126
12METMETLYSLYSBB1 - 1041 - 104
22METMETLYSLYSFF1 - 1041 - 104
13METMETCYSCYSCC17 - 1122 - 97
23METMETCYSCYSGG17 - 1122 - 97
14PROPROGLNGLNDD61 - 20910 - 158
24PROPROGLNGLNHH61 - 20910 - 158

NCS ensembles :
ID
1
2
3
4

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Components

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Protein , 4 types, 8 molecules AEBFCGDH

#1: Protein Bromodomain-containing protein 4 / Protein HUNK1


Mass: 14899.109 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Production host: Escherichia coli (E. coli) / References: UniProt: O60885
#2: 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.: 2
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
#3: 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.: 2
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
#4: Protein von Hippel-Lindau disease tumor suppressor / Protein G7 / pVHL


Mass: 18702.291 Da / Num. of mol.: 2
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

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Non-polymers , 3 types, 69 molecules

#5: Chemical ChemComp-QLX / (2~{S},4~{R})-~{N}-[(1~{S})-3-[2-[2-[2-[2-[2-[(9~{S})-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0^{2,6}]trideca-2(6),4,7,10,12-pentaen-9-yl]ethanoylamino]ethoxy]ethoxy]ethoxy]ethylamino]-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]-3-oxidanylidene-propyl]-1-[(2~{R})-3-methyl-2-(3-methyl-1,2-oxazol-5-yl)butanoyl]-4-oxidanyl-pyrrolidine-2-carboxamide


Mass: 1097.738 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C54H65ClN10O9S2 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-MLI / MALONATE ION


Mass: 102.046 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H2O4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 66 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.95 Å3/Da / Density % sol: 58.28 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.2M sodium malonate dibasic monohydrate, 20% (w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 4, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→65.8 Å / Num. obs: 29056 / % possible obs: 91 % / Redundancy: 5.3 % / CC1/2: 0.999 / Rmerge(I) obs: 0.081 / Rpim(I) all: 0.039 / Rrim(I) all: 0.089 / Net I/σ(I): 12.3
Reflection shell

Diffraction-ID: 1 / Redundancy: 5.1 %

Resolution (Å)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.704-2.891.24737214530.4630.6121.3851.346.9
7.821-65.8020.031748514560.9990.0150.03534.799.9

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5t35

5t35


Resolution: 2.7→65.8 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.933 / SU B: 34.145 / SU ML: 0.297 / SU R Cruickshank DPI: 0.2937 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.367 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2426 1512 5.2 %RANDOM
Rwork0.1878 ---
obs0.1905 27542 82.55 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 188.52 Å2 / Biso mean: 85.034 Å2 / Biso min: 46.61 Å2
Baniso -1Baniso -2Baniso -3
1--1.36 Å2-0.68 Å2-0 Å2
2---1.36 Å2-0 Å2
3---4.41 Å2
Refinement stepCycle: final / Resolution: 2.7→65.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7099 0 159 66 7324
Biso mean--75.1 65.35 -
Num. residues----906
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0137455
X-RAY DIFFRACTIONr_bond_other_d0.0020.0176867
X-RAY DIFFRACTIONr_angle_refined_deg1.7311.6510148
X-RAY DIFFRACTIONr_angle_other_deg1.4811.60115809
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9675899
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.43721.885382
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.937151170
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.6991550
X-RAY DIFFRACTIONr_chiral_restr0.0930.2971
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.028753
X-RAY DIFFRACTIONr_gen_planes_other0.0070.021677
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A33820.09
12E33820.09
21B27000.12
22F27000.12
31C25160.11
32G25160.11
41D47030.09
42H47030.09
LS refinement shellResolution: 2.704→2.774 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.324 12 -
Rwork0.286 108 -
all-120 -
obs--4.61 %
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)
11.88511.4544-0.32345.0322-1.18550.4546-0.08150.0312-0.10070.31050.0038-0.2989-0.16410.07130.07770.39210.0010.0360.22250.02820.030324.92434.716-18.177
22.2716-0.75470.75912.0978-1.86683.0240.0322-0.4147-0.14660.1556-0.0895-0.26550.33430.02590.05730.31730.0184-0.06770.49990.1150.0903-3.212-17.46716.613
33.01270.5275-0.02581.43390.2422.61480.1145-0.37070.11580.14530.0080.0608-0.0733-0.3893-0.12250.20660.03870.0030.45180.05380.0193-15.646-5.5489.679
41.24390.9748-0.12251.27510.30580.33150.00710.20150.1404-0.14210.04450.0709-0.1266-0.1407-0.05160.20570.10870.06260.33560.09170.0401-3.89813.184-9.309
52.6789-1.4927-1.01383.15790.04860.70590.10130.2887-0.1676-0.3682-0.16440.1584-0.0335-0.23690.06320.24790.0563-0.03590.3825-0.10280.0356-15.6324.84720.359
62.1653-0.31910.13122.16161.1662.50190.23560.4003-0.4751-0.1932-0.1868-0.09980.52190.0668-0.04880.23690.123-0.00990.3027-0.04280.125231.071-11.14-12.444
73.7399-0.5483-0.78510.50580.85962.05920.03920.27480.1833-0.05140.0077-0.18760.07390.258-0.04680.05690.09870.0860.31160.06160.20437.293.406-4.711
82.2715-0.4763-0.54271.2280.53310.89490.0519-0.27530.31160.08190.1357-0.3508-0.15610.1959-0.18760.1389-0.01880.00880.2842-0.07730.123919.91918.03312.161
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A351 - 458
2X-RAY DIFFRACTION2B1 - 104
3X-RAY DIFFRACTION3C16 - 112
4X-RAY DIFFRACTION4D61 - 301
5X-RAY DIFFRACTION5E351 - 459
6X-RAY DIFFRACTION6F1 - 104
7X-RAY DIFFRACTION7G17 - 201
8X-RAY DIFFRACTION8H61 - 301

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