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- PDB-6zhc: PROTAC6 mediated complex of VHL:EloB:EloC and Bcl-xL -

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Basic information

Entry
Database: PDB / ID: 6zhc
TitlePROTAC6 mediated complex of VHL:EloB:EloC and Bcl-xL
Components
  • Bcl-2-like protein 1
  • Elongin-B
  • Elongin-C
  • von Hippel-Lindau disease tumor suppressor
KeywordsTRANSCRIPTION / PROTAC complex / targeted degradation / ubiquitin ligase / bifunctional ligand / E3 ligase / Bcl-xL
Function / homology
Function and homology information


apoptotic process in bone marrow cell / regulation of cellular response to hypoxia / The NLRP1 inflammasome / dendritic cell apoptotic process / SARS-CoV-1-mediated effects on programmed cell death / dendritic cell proliferation / positive regulation of mononuclear cell proliferation / RHOBTB3 ATPase cycle / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / negative regulation of receptor signaling pathway via JAK-STAT ...apoptotic process in bone marrow cell / regulation of cellular response to hypoxia / The NLRP1 inflammasome / dendritic cell apoptotic process / SARS-CoV-1-mediated effects on programmed cell death / dendritic cell proliferation / positive regulation of mononuclear cell proliferation / RHOBTB3 ATPase cycle / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / negative regulation of receptor signaling pathway via JAK-STAT / negative regulation of dendritic cell apoptotic process / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / transcription elongation factor activity / target-directed miRNA degradation / VCB complex / elongin complex / negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / negative regulation of execution phase of apoptosis / fertilization / regulation of growth / regulation of mitochondrial membrane permeability / Replication of the SARS-CoV-1 genome / Cul5-RING ubiquitin ligase complex / Bcl-2 family protein complex / NFE2L2 regulating tumorigenic genes / intracellular membraneless organelle / Cul2-RING ubiquitin ligase complex / apoptotic mitochondrial changes / response to cycloheximide / STAT5 activation downstream of FLT3 ITD mutants / cellular response to alkaloid / SUMOylation of ubiquitinylation proteins / hepatocyte apoptotic process / negative regulation of release of cytochrome c from mitochondria / negative regulation of reproductive process / negative regulation of developmental process / negative regulation of intrinsic apoptotic signaling pathway / germ cell development / BH3 domain binding / negative regulation of transcription elongation by RNA polymerase II / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / negative regulation of anoikis / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / ectopic germ cell programmed cell death / Tat-mediated elongation of the HIV-1 transcript / negative regulation of protein localization to plasma membrane / Formation of HIV-1 elongation complex containing HIV-1 Tat / ubiquitin-like ligase-substrate adaptor activity / negative regulation of signal transduction / Formation of HIV elongation complex in the absence of HIV Tat / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / ovarian follicle development / extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of TORC1 signaling / RNA Polymerase II Pre-transcription Events / negative regulation of autophagy / response to cytokine / release of cytochrome c from mitochondria / regulation of mitochondrial membrane potential / regulation of cytokinesis / epithelial cell proliferation / transcription corepressor binding / TP53 Regulates Transcription of DNA Repair Genes / positive regulation of cell differentiation / transcription initiation at RNA polymerase II promoter / cellular response to amino acid stimulus / transcription elongation by RNA polymerase II / Vif-mediated degradation of APOBEC3G / cellular response to gamma radiation / 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 / synaptic vesicle membrane / endocytosis / RAS processing / intrinsic apoptotic signaling pathway in response to DNA damage / male gonad development / 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 / channel activity / regulation of gene expression / ubiquitin-dependent protein catabolic process / protein-containing complex assembly / nuclear membrane / protein-macromolecule adaptor activity / DNA-binding transcription factor binding / spermatogenesis / neuron apoptotic process
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 / Apoptosis regulator, Bcl-X / Apoptosis regulator, Bcl-2/ BclX ...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 / Apoptosis regulator, Bcl-X / Apoptosis regulator, Bcl-2/ BclX / Apoptosis regulator, Bcl-2, BH4 motif, conserved site / Apoptosis regulator, Bcl-2 family BH4 motif signature. / Apoptosis regulator, Bcl-2 protein, BH4 / Bcl-2 homology region 4 / Apoptosis regulator, Bcl-2 family BH4 motif profile. / BH4 Bcl-2 homology region 4 / Elongin-C / Elongin B / Apoptosis regulator, Bcl-2, BH3 motif, conserved site / Apoptosis regulator, Bcl-2 family BH3 motif signature. / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / Apoptosis regulator, Bcl-2, BH1 motif, conserved site / Apoptosis regulator, Bcl-2 family BH1 motif signature. / Apoptosis regulator, Bcl-2, BH2 motif, conserved site / Apoptosis regulator, Bcl-2 family BH2 motif signature. / Bcl-2 family / BCL (B-Cell lymphoma); contains BH1, BH2 regions / Bcl2-like / Bcl-2, Bcl-2 homology region 1-3 / Apoptosis regulator proteins, Bcl-2 family / BCL2-like apoptosis inhibitors family profile. / Bcl-2-like superfamily / SKP1/BTB/POZ domain superfamily / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
IODIDE ION / Chem-QL8 / von Hippel-Lindau disease tumor suppressor / Bcl-2-like protein 1 / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.92 Å
AuthorsChung, C.
CitationJournal: Acs Chem.Biol. / Year: 2020
Title: Structural Insights into PROTAC-Mediated Degradation of Bcl-xL.
Authors: Chung, C.W. / Dai, H. / Fernandez, E. / Tinworth, C.P. / Churcher, I. / Cryan, J. / Denyer, J. / Harling, J.D. / Konopacka, A. / Queisser, M.A. / Tame, C.J. / Watt, G. / Jiang, F. / Qian, D. / Benowitz, A.B.
History
DepositionJun 22, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 5, 2020Provider: repository / Type: Initial release
Revision 1.1Sep 30, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Jan 24, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: atom_type / chem_comp_atom ...atom_type / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z ..._atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
AAA: von Hippel-Lindau disease tumor suppressor
BBB: Elongin-B
CCC: Elongin-C
DDD: Bcl-2-like protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,56143
Polymers65,8244
Non-polymers4,73639
Water8,287460
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area13990 Å2
ΔGint-6 kcal/mol
Surface area23710 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.990, 101.180, 106.930
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 4 types, 4 molecules AAABBBCCCDDD

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


Mass: 18012.527 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VHL / Plasmid: pET30a / Production host: Escherichia coli (E. coli) / References: UniProt: P40337
#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: 12088.736 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOB, TCEB2 / Plasmid: pCDFDuet1 / 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: 10843.420 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1 / Plasmid: pCDFDuet1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15369
#4: Protein Bcl-2-like protein 1 / Bcl2-L-1 / Apoptosis regulator Bcl-X


Mass: 24879.371 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BCL2L1, BCL2L, BCLX / Production host: Escherichia coli (E. coli) / References: UniProt: Q07817

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Non-polymers , 5 types, 499 molecules

#5: Chemical ChemComp-QL8 / 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1~{H}-isoquinolin-2-yl]-5-[3-[4-[3-[2-[2-[2-[2-[2-[3-[[(2~{S})-3,3-dimethyl-1-[(2~{S},4~{R})-2-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylcarbamoyl]-4-oxidanyl-pyrrolidin-1-yl]-1-oxidanylidene-butan-2-yl]amino]-3-oxidanylidene-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]prop-1-ynyl]phenoxy]propyl]-1,3-thiazole-4-carboxylic acid


Mass: 1329.603 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C68H80N8O14S3 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 17 / Source method: obtained synthetically / Formula: C2H6O2
#7: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C3H8O3
#8: Chemical
ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: I
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 460 / 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: 58.36 %
Crystal growTemperature: 291 K / Method: vapor diffusion / pH: 6.5
Details: 0.2 M Potassium iodide, 0.1 M MES pH 6.5, 23% PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Feb 15, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 1.92→47.27 Å / Num. obs: 59379 / % possible obs: 99.9 % / Redundancy: 6.5 % / Rmerge(I) obs: 0.079 / Net I/σ(I): 15.1
Reflection shellResolution: 1.92→1.97 Å / Redundancy: 5.7 % / Rmerge(I) obs: 0.638 / Mean I/σ(I) obs: 2.5 / Num. unique obs: 3945 / % possible all: 99.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0257refinement
XDSdata reduction
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1LM8,1MAZ

1lm8

1maz


Resolution: 1.92→47.27 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.958 / SU B: 2.726 / SU ML: 0.078 / Cross valid method: FREE R-VALUE / ESU R: 0.119 / ESU R Free: 0.112
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.1957 2910 4.901 %
Rwork0.1694 56468 -
all0.171 --
obs-59378 99.802 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL PLUS MASK
Displacement parametersBiso mean: 33.4 Å2
Baniso -1Baniso -2Baniso -3
1-0.019 Å20 Å2-0 Å2
2---0.039 Å20 Å2
3---0.02 Å2
Refinement stepCycle: LAST / Resolution: 1.92→47.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3957 0 227 460 4644
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0134429
X-RAY DIFFRACTIONr_bond_other_d0.0020.0174120
X-RAY DIFFRACTIONr_angle_refined_deg1.2521.6815991
X-RAY DIFFRACTIONr_angle_other_deg1.191.5999571
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4185530
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.71821.529242
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.85815724
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.6741536
X-RAY DIFFRACTIONr_chiral_restr0.0550.2543
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.024892
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02951
X-RAY DIFFRACTIONr_nbd_refined0.1940.2858
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1750.23707
X-RAY DIFFRACTIONr_nbtor_refined0.1610.22068
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0850.21765
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1650.2414
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.3130.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2190.214
X-RAY DIFFRACTIONr_nbd_other0.2120.267
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1510.224
X-RAY DIFFRACTIONr_mcbond_it2.414.3042054
X-RAY DIFFRACTIONr_mcbond_other2.4064.3032053
X-RAY DIFFRACTIONr_mcangle_it3.6379.6332588
X-RAY DIFFRACTIONr_mcangle_other3.6369.6362589
X-RAY DIFFRACTIONr_scbond_it3.2964.8982375
X-RAY DIFFRACTIONr_scbond_other3.2954.92376
X-RAY DIFFRACTIONr_scangle_it5.20510.5993392
X-RAY DIFFRACTIONr_scangle_other5.20410.6023393
X-RAY DIFFRACTIONr_lrange_it7.32940.1695102
X-RAY DIFFRACTIONr_lrange_other7.1739.4724970
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.92-1.970.2792010.2434101X-RAY DIFFRACTION99.3993
1.97-2.0240.2462340.2264014X-RAY DIFFRACTION99.812
2.024-2.0820.232020.2063883X-RAY DIFFRACTION100
2.082-2.1460.2332420.193784X-RAY DIFFRACTION100
2.146-2.2170.1922280.1783638X-RAY DIFFRACTION99.9741
2.217-2.2950.2121870.1623592X-RAY DIFFRACTION99.9735
2.295-2.3810.2251570.1633464X-RAY DIFFRACTION99.9724
2.381-2.4780.2151750.1623317X-RAY DIFFRACTION99.8856
2.478-2.5880.1991570.1673215X-RAY DIFFRACTION99.8815
2.588-2.7140.1861640.1623039X-RAY DIFFRACTION99.9376
2.714-2.8610.1821460.1582929X-RAY DIFFRACTION99.8701
2.861-3.0340.2071340.1532765X-RAY DIFFRACTION99.8278
3.034-3.2430.1861230.1672621X-RAY DIFFRACTION99.6007
3.243-3.5030.2191110.1682439X-RAY DIFFRACTION99.6873
3.503-3.8360.1931150.1632236X-RAY DIFFRACTION99.8302
3.836-4.2870.15930.1482075X-RAY DIFFRACTION99.7699
4.287-4.9480.15770.1371833X-RAY DIFFRACTION99.5829
4.948-6.0530.185790.1791544X-RAY DIFFRACTION99.4485
6.053-8.5310.211500.1981247X-RAY DIFFRACTION99.6925
8.531-47.270.174350.174732X-RAY DIFFRACTION98.3333

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