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- PDB-8beb: Ternary complex between VCB, BRD4-BD1 and PROTAC 49 -

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Basic information

Entry
Database: PDB / ID: 8beb
TitleTernary complex between VCB, BRD4-BD1 and PROTAC 49
Components
  • Bromodomain-containing protein 4
  • Elongin-B
  • Elongin-C
  • von Hippel-Lindau disease tumor suppressor
KeywordsLIGASE / PROTAC / degrader / complex / E3 ligase / VHL / VCB
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, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / Elongin C; Chain C, domain 1 / 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 ...von Hippel-Lindau disease tumour suppressor, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / Elongin C; Chain C, domain 1 / 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-like / Histone Acetyltransferase; Chain A / 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 / Up-down Bundle / Immunoglobulin-like / Sandwich / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-QIK / 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 / molecular replacement / Resolution: 3.18 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 21, 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)57,6146
Polymers56,5254
Non-polymers1,0902
Water543
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, isothermal titration calorimetry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6120 Å2
ΔGint-56 kcal/mol
Surface area22180 Å2
Unit cell
Length a, b, c (Å)79.754, 79.754, 184.930
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121

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Components

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Protein , 4 types, 4 molecules ABCD

#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: 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
#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.: 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
#3: Protein von Hippel-Lindau disease tumor suppressor / Protein G7 / pVHL


Mass: 18702.291 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 Bromodomain-containing protein 4 / Protein HUNK1


Mass: 15099.380 Da / Num. of mol.: 1
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

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Non-polymers , 3 types, 5 molecules

#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-QIK / (2~{S},4~{R})-~{N}-[(1~{S})-3-[4-[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]butylamino]-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: 993.634 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C50H57ClN10O6S2 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / 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: 3 Å3/Da / Density % sol: 59.05 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 1.8M ammonium sulfate, 4% (w/v) glycerol, 0.1M bis-Tris pH5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.97626 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 21, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97626 Å / Relative weight: 1
ReflectionResolution: 3.18→64.7 Å / Num. obs: 9832 / % possible obs: 85.4 % / Redundancy: 18.3 % / CC1/2: 0.995 / Rmerge(I) obs: 0.353 / Rpim(I) all: 0.084 / Rrim(I) all: 0.363 / Net I/σ(I): 9.4
Reflection shellResolution: 3.18→3.346 Å / Redundancy: 20.9 % / Rmerge(I) obs: 2.206 / Num. unique obs: 493 / CC1/2: 0.512 / Rpim(I) all: 0.492 / Rrim(I) all: 2.261 / % possible all: 41.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
REFMAC5.8.0352refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5nw1, 3mxf

5nw1

3mxf


Resolution: 3.18→64.7 Å / Cor.coef. Fo:Fc: 0.907 / Cor.coef. Fo:Fc free: 0.881 / SU B: 61.758 / SU ML: 0.447 / SU R Cruickshank DPI: 0.4791 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.593 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2739 462 4.7 %RANDOM
Rwork0.2179 ---
obs0.2207 9370 81.66 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 144.5 Å2 / Biso mean: 71.841 Å2 / Biso min: 8.96 Å2
Baniso -1Baniso -2Baniso -3
1--0.23 Å2-0.11 Å20 Å2
2---0.23 Å20 Å2
3---0.74 Å2
Refinement stepCycle: final / Resolution: 3.18→64.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3599 0 74 3 3676
Biso mean--88.13 21.64 -
Num. residues----455
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0123771
X-RAY DIFFRACTIONr_bond_other_d0.0020.0163385
X-RAY DIFFRACTIONr_angle_refined_deg1.5571.665149
X-RAY DIFFRACTIONr_angle_other_deg0.5151.5577898
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.85450
X-RAY DIFFRACTIONr_dihedral_angle_2_deg11.7346.42928
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.21110600
X-RAY DIFFRACTIONr_chiral_restr0.0780.2577
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.024229
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02711
LS refinement shellResolution: 3.18→3.262 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.278 4 -
Rwork0.308 127 -
all-131 -
obs--15.18 %
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)
11.0269-0.80780.26712.06510.22990.2217-0.03290.03940.1485-0.0459-0.0704-0.0063-0.047-0.05340.10330.26360.05280.05410.24610.01170.173221.650832.423719.4947
21.28260.43041.08170.6847-0.79953.42310.0071-0.0692-0.12840.00180.0389-0.08820.0047-0.1741-0.0460.20570.074-0.00350.1531-0.03220.156525.955714.826521.0623
31.14170.1282-0.30890.67190.4980.5323-0.00760.2099-0.32460.1420.0836-0.22320.065-0.0536-0.0760.23720.0975-0.04070.2988-0.06010.225818.1407-1.2477-0.1521
40.874-0.4467-0.07831.00970.55410.5314-0.1308-0.01910.0274-0.00240.0237-0.0949-0.1055-0.08690.10710.22890.0378-0.03610.291-0.04690.160327.3429-9.4689-24.411
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 104
2X-RAY DIFFRACTION2B17 - 112
3X-RAY DIFFRACTION3C62 - 202
4X-RAY DIFFRACTION4D44 - 167

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