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- PDB-7zwq: Crystal structure of human BCL6 BTB domain in complex with compound 10 -

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Basic information

Entry
Database: PDB / ID: 7zwq
TitleCrystal structure of human BCL6 BTB domain in complex with compound 10
ComponentsB-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 plasma cell differentiation / negative regulation of T-helper 2 cell differentiation / negative regulation of isotype switching to IgE isotypes / 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 plasma cell differentiation / negative regulation of T-helper 2 cell differentiation / negative regulation of isotype switching to IgE isotypes / 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 / positive regulation of cell motility / negative regulation of B cell apoptotic process / negative regulation of Rho protein signal transduction / erythrocyte development / FOXO-mediated transcription of cell death genes / regulation of cell differentiation / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / regulation of T cell proliferation / B cell proliferation / negative regulation of cellular senescence / negative regulation of cell-matrix adhesion / negative regulation of Notch signaling pathway / regulation of immune response / Rho protein signal transduction / positive regulation of B cell proliferation / positive regulation of neuron differentiation / regulation of cytokine production / cell-matrix adhesion / transcription corepressor binding / cell motility / negative regulation of cell growth / chromatin DNA binding / DNA-binding transcription repressor activity, RNA polymerase II-specific / cell morphogenesis / sequence-specific double-stranded DNA binding / intracellular protein localization / heterochromatin formation / regulation of cell population proliferation / actin cytoskeleton organization / regulation of inflammatory response / Interleukin-4 and Interleukin-13 signaling / spermatogenesis / sequence-specific DNA binding / DNA-binding transcription factor binding / transcription by RNA polymerase II / positive regulation of apoptotic process / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / inflammatory response / negative regulation of DNA-templated transcription / DNA damage response / chromatin binding / nucleolus / negative regulation of transcription by RNA polymerase II / Golgi apparatus / zinc ion binding / nucleoplasm / identical protein binding / nucleus
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 / Zinc finger C2H2 type domain signature. / SKP1/BTB/POZ domain superfamily / Zinc finger C2H2-type
Similarity search - Domain/homology
Chem-K4O / B-cell lymphoma 6 protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.65 Å
AuthorsRodrigues, M.J. / 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,65013
Polymers16,4991
Non-polymers1,15112
Water2,216123
1
A: B-cell lymphoma 6 protein
hetero molecules

A: B-cell lymphoma 6 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,30026
Polymers32,9982
Non-polymers2,30324
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation12_565x,x-y+1,-z+1/61
Buried area7450 Å2
ΔGint7 kcal/mol
Surface area13290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.160, 67.160, 165.130
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11A-360-

HOH

21A-381-

HOH

31A-422-

HOH

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Components

#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: 16498.953 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: Chemical ChemComp-K4O / ~{N}-[(2-fluorophenyl)methyl]-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine


Mass: 257.266 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H12FN5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 123 / Source method: isolated from a natural source / Formula: H2O
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: 3.26 Å3/Da / Density % sol: 62.25 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 1.5 microliter of BCL6-BTB at 10 mg/mL plus 1.5 microliter of a crystallisation solution consisting of 0.1 M Tris pH 7.5 and 0.80 M Na/K Tartrate, against 300 microliter of crystallisation solution.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9159 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jul 15, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9159 Å / Relative weight: 1
ReflectionResolution: 1.65→47.55 Å / Num. obs: 27423 / % possible obs: 100 % / Redundancy: 12 % / Biso Wilson estimate: 36.89 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.064 / Rpim(I) all: 0.019 / Rrim(I) all: 0.067 / Net I/σ(I): 15.8 / Num. measured all: 329181 / Scaling rejects: 345
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.65-1.68103.0661333413300.3431.0083.2320.8100
9.04-47.5510.50.04823492230.9980.0150.0549.799.3

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
PHASERphasing
BUSTER2.10.3refinement
PDB_EXTRACT3.24data extraction
DIALSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3BIM

3bim


Resolution: 1.65→19.99 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.953 / SU R Cruickshank DPI: 0.074 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.08 / SU Rfree Blow DPI: 0.08 / SU Rfree Cruickshank DPI: 0.075
RfactorNum. reflection% reflectionSelection details
Rfree0.207 1373 5.02 %RANDOM
Rwork0.183 ---
obs0.184 27364 99.9 %-
Displacement parametersBiso max: 139.63 Å2 / Biso mean: 45.53 Å2 / Biso min: 25.58 Å2
Baniso -1Baniso -2Baniso -3
1--2.4734 Å20 Å20 Å2
2---2.4734 Å20 Å2
3---4.9467 Å2
Refine analyzeLuzzati coordinate error obs: 0.22 Å
Refinement stepCycle: final / Resolution: 1.65→19.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1023 0 94 129 1246
Biso mean--55.71 62.16 -
Num. residues----131
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d424SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes262HARMONIC5
X-RAY DIFFRACTIONt_it1213HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion152SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies14HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1642SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1213HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg1631HARMONIC20.97
X-RAY DIFFRACTIONt_omega_torsion3.54
X-RAY DIFFRACTIONt_other_torsion14
LS refinement shellResolution: 1.65→1.66 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2767 24 4.38 %
Rwork0.2469 524 -
all0.2483 548 -
obs--99.24 %
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)
14.41310.5118-2.95111.7277-0.6635.7630.12180.15160.31970.10670.0059-0.0374-0.43920.3545-0.1277-0.058-0.0394-0.0198-0.04320.0337-0.0472-26.500328.55110.0419
21.8735-0.6636-0.20565.2571-1.6594.5830.0672-0.2421-0.10280.47170.2040.5025-0.0581-0.4917-0.2712-0.0285-0.02210.06240.00180.049-0.0172-40.548315.933826.4825
31.61830.95140.35252.6528-0.64162.51870.1359-0.1284-0.13880.2822-0.1105-0.01440.2410.0419-0.02540.0092-0.0271-0.01-0.09340.0263-0.0301-30.088211.317526.5077
44.4142-0.13210.23288.1677-1.41880.3778-0.04820.2586-0.13190.2753-0.2119-0.7046-0.06440.11780.2601-0.0246-0.0063-0.07920.00410.10270.1357-13.705113.56529.7597
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|-1 - 27}A-1 - 27
2X-RAY DIFFRACTION2{A|28 - 46}A28 - 46
3X-RAY DIFFRACTION3{A|47 - 114}A47 - 114
4X-RAY DIFFRACTION4{A|115 - 129}A115 - 129

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