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- PDB-7zwu: Crystal structure of human BCL6 BTB domain in complex with compound 15 -

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Basic information

Entry
Database: PDB / ID: 7zwu
TitleCrystal structure of human BCL6 BTB domain in complex with compound 15
Components
  • ALA-TRP-VAL-ILE-PRO-ALA
  • B-cell lymphoma 6 protein
KeywordsTRANSCRIPTION / Inhibitor / Cancer
Function / homology
Function and homology information


regulation of memory T cell differentiation / negative regulation of mitotic cell cycle DNA replication / intronic transcription regulatory region sequence-specific DNA binding / negative regulation of isotype switching to IgE isotypes / negative regulation of plasma cell differentiation / negative regulation of T-helper 2 cell differentiation / isotype switching to IgE isotypes / negative regulation of mast cell cytokine production / regulation of germinal center formation / negative regulation of mononuclear cell proliferation ...regulation of memory T cell differentiation / negative regulation of mitotic cell cycle DNA replication / intronic transcription regulatory region sequence-specific DNA binding / negative regulation of isotype switching to IgE isotypes / negative regulation of plasma cell differentiation / negative regulation of T-helper 2 cell differentiation / isotype switching to IgE isotypes / negative regulation of mast cell cytokine production / regulation of germinal center formation / negative regulation of mononuclear cell proliferation / plasma cell differentiation / paraspeckles / germinal center formation / regulation of immune system process / pyramidal neuron differentiation / type 2 immune response / T-helper 2 cell differentiation / positive regulation of regulatory T cell differentiation / negative regulation of B cell apoptotic process / positive regulation of cell motility / negative regulation of Rho protein signal transduction / FOXO-mediated transcription of cell death genes / negative regulation of cell-matrix adhesion / regulation of T cell proliferation / regulation of cell differentiation / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / negative regulation of Notch signaling pathway / B cell proliferation / negative regulation of cellular senescence / Rho protein signal transduction / regulation of immune response / erythrocyte development / positive regulation of B cell proliferation / regulation of cytokine production / positive regulation of neuron differentiation / cell-matrix adhesion / transcription corepressor binding / cell motility / cell morphogenesis / negative regulation of cell growth / chromatin DNA binding / heterochromatin formation / DNA-binding transcription repressor activity, RNA polymerase II-specific / sequence-specific double-stranded DNA binding / protein localization / regulation of cell population proliferation / regulation of inflammatory response / actin cytoskeleton organization / spermatogenesis / Interleukin-4 and Interleukin-13 signaling / DNA-binding transcription factor binding / sequence-specific DNA binding / transcription by RNA polymerase II / inflammatory response / positive regulation of apoptotic process / DNA-binding transcription factor activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / negative regulation of DNA-templated transcription / DNA damage response / chromatin binding / nucleolus / Golgi apparatus / negative regulation of transcription by RNA polymerase II / nucleoplasm / identical protein binding / nucleus / metal ion binding
Similarity search - Function
BTB/POZ domain / BTB domain profile. / Zinc finger, C2H2 type / Broad-Complex, Tramtrack and Bric a brac / BTB/POZ domain / zinc finger / Zinc finger C2H2 type domain profile. / Zinc finger C2H2 superfamily / SKP1/BTB/POZ domain superfamily / Zinc finger C2H2 type domain signature. / Zinc finger C2H2-type
Similarity search - Domain/homology
Chem-K8R / B-cell lymphoma 6 protein
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.56 Å
AuthorsCollie, G.W. / Le Bihan, Y.-V. / van Montfort, R.L.M.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Cancer Research UKC309/A11566 United Kingdom
CitationJournal: Sci Rep / Year: 2022
Title: Discovering cell-active BCL6 inhibitors: effectively combining biochemical HTS with multiple biophysical techniques, X-ray crystallography and cell-based assays.
Authors: Pierrat, O.A. / Liu, M. / Collie, G.W. / Shetty, K. / Rodrigues, M.J. / Le Bihan, Y.V. / Gunnell, E.A. / McAndrew, P.C. / Stubbs, M. / Rowlands, M.G. / Yahya, N. / Shehu, E. / Talbot, R. / ...Authors: Pierrat, O.A. / Liu, M. / Collie, G.W. / Shetty, K. / Rodrigues, M.J. / Le Bihan, Y.V. / Gunnell, E.A. / McAndrew, P.C. / Stubbs, M. / Rowlands, M.G. / Yahya, N. / Shehu, E. / Talbot, R. / Pickard, L. / Bellenie, B.R. / Cheung, K.J. / Drouin, L. / Innocenti, P. / Woodward, H. / Davis, O.A. / Lloyd, M.G. / Varela, A. / Huckvale, R. / Broccatelli, F. / Carter, M. / Galiwango, D. / Hayes, A. / Raynaud, F.I. / Bryant, C. / Whittaker, S. / Rossanese, O.W. / Hoelder, S. / Burke, R. / van Montfort, R.L.M.
History
DepositionMay 19, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 16, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 31, 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

Downloads & links

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Assembly

Deposited unit
A: B-cell lymphoma 6 protein
B: ALA-TRP-VAL-ILE-PRO-ALA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)16,21513
Polymers15,1932
Non-polymers1,02311
Water2,954164
1
A: B-cell lymphoma 6 protein
B: ALA-TRP-VAL-ILE-PRO-ALA
hetero molecules

A: B-cell lymphoma 6 protein
B: ALA-TRP-VAL-ILE-PRO-ALA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,43126
Polymers30,3854
Non-polymers2,04522
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation12_545x,x-y-1,-z+1/61
Buried area8260 Å2
ΔGint-48 kcal/mol
Surface area14080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.410, 67.410, 165.130
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AB

#1: Protein B-cell lymphoma 6 protein / BCL-6 / B-cell lymphoma 5 protein / BCL-5 / Protein LAZ-3 / Zinc finger and BTB domain-containing ...BCL-6 / B-cell lymphoma 5 protein / BCL-5 / Protein LAZ-3 / Zinc finger and BTB domain-containing protein 27 / Zinc finger protein 51


Mass: 14536.915 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BCL6, BCL5, LAZ3, ZBTB27, ZNF51 / Plasmid: pET48b / Production host: Escherichia coli BL21 (bacteria) / Variant (production host): AI / References: UniProt: P41182
#2: Protein/peptide ALA-TRP-VAL-ILE-PRO-ALA


Mass: 655.784 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 5 types, 175 molecules

#3: Chemical ChemComp-K8R / ~{N}-(3-morpholin-4-ylpropyl)-2-(naphthalen-1-ylamino)-1,3-thiazole-4-carboxamide


Mass: 396.506 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H24N4O2S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 164 / 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: 3.56 Å3/Da / Density % sol: 65.49 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 2 microliter of the BCL6-BTB/WVIP complex at 4 mg/mL plus 1 microliter of a crystallisation solution consisting of 1 M K2HPO4, 0.7 M NaH2PO4, 75 mM sodium acetate buffer pH 4.5 and 2 % DMSO, ...Details: 2 microliter of the BCL6-BTB/WVIP complex at 4 mg/mL plus 1 microliter of a crystallisation solution consisting of 1 M K2HPO4, 0.7 M NaH2PO4, 75 mM sodium acetate buffer pH 4.5 and 2 % DMSO, against 350 microliter of crystallisation solution.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.966 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Aug 27, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.966 Å / Relative weight: 1
ReflectionResolution: 1.56→47.667 Å / Num. obs: 32153 / % possible obs: 98.8 % / Redundancy: 11.2 % / Biso Wilson estimate: 20.29 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.1 / Net I/σ(I): 14.6
Reflection shellResolution: 1.56→1.587 Å / Rmerge(I) obs: 0.871 / Mean I/σ(I) obs: 2.5 / Num. unique obs: 1593 / CC1/2: 0.381

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimlessdata scaling
PHASERphasing
BUSTER2.10.3refinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3BIM

3bim


Resolution: 1.56→20.48 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.962 / SU R Cruickshank DPI: 0.055 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.061 / SU Rfree Blow DPI: 0.062 / SU Rfree Cruickshank DPI: 0.057
RfactorNum. reflection% reflectionSelection details
Rfree0.177 1561 4.86 %RANDOM
Rwork0.157 ---
obs0.158 32132 98.8 %-
Displacement parametersBiso max: 85.4 Å2 / Biso mean: 26.13 Å2 / Biso min: 11.41 Å2
Baniso -1Baniso -2Baniso -3
1--0.535 Å20 Å20 Å2
2---0.535 Å20 Å2
3---1.07 Å2
Refine analyzeLuzzati coordinate error obs: 0.18 Å
Refinement stepCycle: final / Resolution: 1.56→20.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1013 0 62 174 1249
Biso mean--41.32 43.79 -
Num. residues----131
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d440SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes228HARMONIC5
X-RAY DIFFRACTIONt_it1211HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion161SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies22HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1605SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1211HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg1639HARMONIC20.97
X-RAY DIFFRACTIONt_omega_torsion3.29
X-RAY DIFFRACTIONt_other_torsion13.71
LS refinement shellResolution: 1.56→1.57 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2627 28 4.35 %
Rwork0.2463 615 -
all0.2469 643 -
obs--100 %
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)
12.90450.98612.57150.9831.36685.25720.0576-0.1-0.07310.1064-0.0446-0.01620.1451-0.2897-0.0131-0.0292-0.01230.0042-0.0109-0.013-0.036529.2123-27.460212.569
20.4829-0.35320.75262.7277-0.06381.81550.0381-0.04370.05050.22890.0964-0.3563-0.12820.0895-0.13450.0786-0.0233-0.02580.1032-0.04150.081941.3174-14.713327.8095
30.2756-0.1143-0.61952.05591.52731.4327-0.0029-0.2141-0.04370.31890.0508-0.0261-0.05480.1495-0.0479-0.1003-0.0109-0.0107-0.1081-0.0167-0.152939.6935-15.520928.9728
41.05411.0098-0.17092.39910.48391.24910.0662-0.01670.04780.0489-0.0195-0.0012-0.1422-0.0183-0.0466-0.0195-0.01640.0157-0.0548-0.0149-0.032233.3211-10.045124.2
51.56352.14712.64932.632-1.06381.63550.1378-0.2235-0.13290.2223-0.17140.07180.21660.19410.03350.047-0.0550.02370.00840.0011-0.016322.3114-22.551132.438
63.1662.9298-1.50465.4466-2.15032.32770.228-0.19770.23450.3713-0.22740.3144-0.1634-0.1383-0.00060.0006-0.02670.0374-0.0254-0.05170.004423.4741-9.951330.5458
75.86541.5329-1.02217.724-1.62630.2885-0.11860.10730.22740.2831-0.01080.68670.1567-0.26920.1295-0.0109-0.04380.06220.0343-0.07320.082613.41-14.67731.4469
87.43411.72290.8503-0.48862.08170.22650.0932-0.08350.0018-0.03580.03630.18560.05070.0273-0.1295-0.0521-0.0260.00390.0596-0.035-0.003119.4936-31.45292.3307
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|5 - 27}A5 - 27
2X-RAY DIFFRACTION2{A|28 - 40}A28 - 40
3X-RAY DIFFRACTION3{A|41 - 46}A41 - 46
4X-RAY DIFFRACTION4{A|47 - 92}A47 - 92
5X-RAY DIFFRACTION5{A|93 - 101}A93 - 101
6X-RAY DIFFRACTION6{A|102 - 114}A102 - 114
7X-RAY DIFFRACTION7{A|115 - 129}A115 - 129
8X-RAY DIFFRACTION8{B|0 - 5}B0 - 5

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