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- PDB-7okj: Crystal structure of human BCL6 BTB domain in complex with compou... -

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Basic information

Entry
Database: PDB / ID: 7okj
TitleCrystal structure of human BCL6 BTB domain in complex with compound 12c and its enantiomer 12b
Components
  • ALA-TRP-VAL-ILE-PRO-ALA
  • B-cell lymphoma 6 protein
KeywordsTRANSCRIPTION / CANCER / LYMPHOMA / INHIBITOR
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 / pyramidal neuron differentiation / regulation of immune system process / type 2 immune response / positive regulation of regulatory T cell differentiation / T-helper 2 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 / negative regulation of Notch signaling pathway / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / B cell proliferation / regulation of cell differentiation / negative regulation of cellular senescence / Rho protein signal transduction / regulation of immune response / erythrocyte development / heterochromatin formation / 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 / protein localization / negative regulation of cell growth / chromatin DNA binding / DNA-binding transcription repressor activity, RNA polymerase II-specific / sequence-specific double-stranded DNA binding / 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 / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / 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-VHN / Chem-VHZ / B-cell lymphoma 6 protein
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.43 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: J.Med.Chem. / Year: 2021
Title: Into Deep Water: Optimizing BCL6 Inhibitors by Growing into a Solvated Pocket.
Authors: Lloyd, M.G. / Huckvale, R. / Cheung, K.J. / Rodrigues, M.J. / Collie, G.W. / Pierrat, O.A. / Gatti Iou, M. / Carter, M. / Davis, O.A. / McAndrew, P.C. / Gunnell, E. / Le Bihan, Y.V. / ...Authors: Lloyd, M.G. / Huckvale, R. / Cheung, K.J. / Rodrigues, M.J. / Collie, G.W. / Pierrat, O.A. / Gatti Iou, M. / Carter, M. / Davis, O.A. / McAndrew, P.C. / Gunnell, E. / Le Bihan, Y.V. / Talbot, R. / Henley, A.T. / Johnson, L.D. / Hayes, A. / Bright, M.D. / Raynaud, F.I. / Meniconi, M. / Burke, R. / van Montfort, R.L.M. / Rossanese, O.W. / Bellenie, B.R. / Hoelder, S.
History
DepositionMay 17, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 8, 2021Provider: repository / Type: Initial release
Revision 1.1Dec 22, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jan 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)16,43012
Polymers15,1932
Non-polymers1,23710
Water3,567198
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)32,85924
Polymers30,3854
Non-polymers2,47420
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation12_535x,x-y-2,-z+1/61
Buried area7540 Å2
ΔGint-66 kcal/mol
Surface area13940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.470, 67.470, 165.490
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-336-

HOH

21A-408-

HOH

31A-480-

HOH

41A-482-

HOH

51A-488-

HOH

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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, 208 molecules

#3: Chemical ChemComp-VHN / (2S)-2-[[6-[(2-chloranyl-3-cyano-pyridin-4-yl)amino]-2-oxidanylidene-1H-quinolin-4-yl]amino]-N-methyl-propanamide / (2S)-2-[[6-[(2-Chloro-3-cyanopyridin-4-yl)amino]-2-oxo-1H-quinolin-4-yl]amino]-N-methylpropanamide


Mass: 396.830 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H17ClN6O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-VHZ / (2R)-2-[[6-[(2-chloranyl-3-cyano-pyridin-4-yl)amino]-2-oxidanylidene-1H-quinolin-4-yl]amino]-N-methyl-propanamide / (2R)-2-[[6-[(2-Chloro-3-cyanopyridin-4-yl)amino]-2-oxo-1H-quinolin-4-yl]amino]-N-methylpropanamide / 142478375


Mass: 396.830 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H17ClN6O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 198 / 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

Crystal growTemperature: 291 K / Method: vapor diffusion / 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: 1.43→58.43 Å / Num. obs: 41944 / % possible obs: 100 % / Redundancy: 11.1 % / Biso Wilson estimate: 19 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.093 / Net I/σ(I): 13.7
Reflection shellResolution: 1.43→1.456 Å / Rmerge(I) obs: 1.094 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 2043 / CC1/2: 0.475

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
XDSdata reduction
PHASERphasing
BUSTER2.10.3 (19-MAR-2020)refinement
PDB_EXTRACT3.24data extraction
autoPROCdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3BIM

3bim


Resolution: 1.43→58.43 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.961 / SU R Cruickshank DPI: 0.047 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.052 / SU Rfree Blow DPI: 0.051 / SU Rfree Cruickshank DPI: 0.046
RfactorNum. reflection% reflectionSelection details
Rfree0.1768 2155 5.14 %RANDOM
Rwork0.1655 ---
obs0.166 41944 100 %-
Displacement parametersBiso max: 83.23 Å2 / Biso mean: 24.6 Å2 / Biso min: 12.11 Å2
Baniso -1Baniso -2Baniso -3
1--0.9369 Å20 Å20 Å2
2---0.9369 Å20 Å2
3---1.8738 Å2
Refine analyzeLuzzati coordinate error obs: 0.17 Å
Refinement stepCycle: final / Resolution: 1.43→58.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1017 0 82 204 1303
Biso mean--32.21 44.27 -
Num. residues----131
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d454SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes257HARMONIC5
X-RAY DIFFRACTIONt_it1239HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion163SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies19HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1403SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1239HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg1690HARMONIC20.95
X-RAY DIFFRACTIONt_omega_torsion3.56
X-RAY DIFFRACTIONt_other_torsion13.34
LS refinement shellResolution: 1.43→1.44 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.2675 36 4.29 %
Rwork0.2308 803 -
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)
11.81590.5521.95570.25160.99783.449-0.0152-0.01090.01670.0951-0.0241-0.00980.1357-0.13080.0393-0.0048-0.0192-0.00760.0179-0.0136-0.006596.4404-27.497512.4509
2-0.2889-0.11870.18771.2780.74011.61210.0450.04680.01540.1320.0801-0.2437-0.0960.2084-0.12510.0018-0.0189-0.02130.0161-0.03290.0049108.8716-15.334927.0044
3-0.1282-0.35681.14161.62071.6614.4342-0.02480.0601-0.01710.17680.0815-0.07290.0060.176-0.05660.0255-0.0218-0.00910.0075-0.01550.0009107.1103-15.747329.0181
41.12941.1417-0.55651.7330.77080.77880.04390.0276-0.0366-0.13730.04910.0355-0.15680.0081-0.0930.0463-0.02560.0218-0.0256-0.0022-0.0041101.8145-6.526717.9143
50.04070.3485-0.28661.19460.13310.58210.10790.0146-0.04860.147-0.0348-0.0623-0.0369-0.0306-0.07310.0326-0.03910.0106-0.0162-0.0175-0.0005100.142-13.160129.3076
60.63180.3521-1.36080.5708-0.18383.49890.0179-0.0089-0.08160.1423-0.130.03980.19030.11750.11210.0383-0.06770.02710.0081-0.015-0.023589.7023-22.570432.6608
71.38741.9892-0.99572.2636-1.43540.96070.1708-0.03440.18770.1522-0.11450.1557-0.0837-0.0236-0.05630.0236-0.03140.0465-0.0235-0.02990.01890.8706-10.290830.7656
82.05031.8329-2.55254.1253-1.39970.0401-0.01640.31980.27450.2919-0.03120.32140.0987-0.08930.0477-0.0196-0.04350.07270.0062-0.04820.0580.8135-14.896131.4135
95.51982.22731.0770.73191.867600.132-0.0781-0.0387-0.08750.03530.04940.0872-0.0052-0.1672-0.0544-0.03630.00890.0616-0.0365-0.009486.6757-31.43782.4162
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 - 68}A47 - 68
5X-RAY DIFFRACTION5{A|69 - 92}A69 - 92
6X-RAY DIFFRACTION6{A|93 - 101}A93 - 101
7X-RAY DIFFRACTION7{A|102 - 114}A102 - 114
8X-RAY DIFFRACTION8{A|115 - 129}A115 - 129
9X-RAY DIFFRACTION9{B|0 - 5}B0 - 5

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