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- PDB-7q7v: Crystal structure of human BCL6 BTB domain in complex with compou... -

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Basic information

Entry
Database: PDB / ID: 7q7v
TitleCrystal structure of human BCL6 BTB domain in complex with compound 12a
ComponentsB-cell lymphoma 6 protein
KeywordsTRANSCRIPTION / 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 / 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 / negative regulation of Notch signaling pathway / B cell proliferation / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / regulation of cell differentiation / 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 / heterochromatin formation / cell morphogenesis / negative regulation of cell growth / chromatin DNA binding / 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 / 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-9GR / B-cell lymphoma 6 protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.81 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: J.Med.Chem. / Year: 2022
Title: Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors.
Authors: Davis, O.A. / Cheung, K.J. / Brennan, A. / Lloyd, M.G. / Rodrigues, M.J. / Pierrat, O.A. / Collie, G.W. / Le Bihan, Y.V. / Huckvale, R. / Harnden, A.C. / Varela, A. / Bright, M.D. / Eve, P. ...Authors: Davis, O.A. / Cheung, K.J. / Brennan, A. / Lloyd, M.G. / Rodrigues, M.J. / Pierrat, O.A. / Collie, G.W. / Le Bihan, Y.V. / Huckvale, R. / Harnden, A.C. / Varela, A. / Bright, M.D. / Eve, P. / Hayes, A. / Henley, A.T. / Carter, M.D. / McAndrew, P.C. / Talbot, R. / Burke, R. / van Montfort, R.L.M. / Raynaud, F.I. / Rossanese, O.W. / Meniconi, M. / Bellenie, B.R. / Hoelder, S.
History
DepositionNov 9, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 15, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 6, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
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

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Assembly

Deposited unit
A: B-cell lymphoma 6 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,1235
Polymers16,4991
Non-polymers6244
Water1,65792
1
A: B-cell lymphoma 6 protein
hetero molecules

A: B-cell lymphoma 6 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,24610
Polymers32,9982
Non-polymers1,2488
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation12_565x,x-y+1,-z+1/61
Buried area4810 Å2
ΔGint-34 kcal/mol
Surface area13710 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.307, 67.307, 166.807
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-322-

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-9GR / 2-chloranyl-4-[[(2R)-2-cyclopropyl-7-methyl-6-oxidanylidene-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-10-yl]amino]pyridine-3-carbonitrile


Mass: 421.880 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H20ClN5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / 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.: 92 / 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: 3.62 Å3/Da / Density % sol: 66.06 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting 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: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 7, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.81→19.63 Å / Num. obs: 21275 / % possible obs: 99.9 % / Redundancy: 23.1 % / Biso Wilson estimate: 33.43 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.135 / Rpim(I) all: 0.029 / Rrim(I) all: 0.138 / Net I/σ(I): 13.4 / Num. measured all: 490474 / Scaling rejects: 33
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
1.81-1.8524.42.6363006612300.5140.5362.6911.6100
9.05-19.6316.60.07134112050.9990.0170.07336.890.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
BUSTER2.10.3 (19-MAR-2020)refinement
XDSdata reduction
Aimless0.5.14data scaling
PHASERphasing
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3BIM

3bim


Resolution: 1.81→19.63 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.958 / SU R Cruickshank DPI: 0.09 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.097 / SU Rfree Blow DPI: 0.093 / SU Rfree Cruickshank DPI: 0.089
RfactorNum. reflection% reflectionSelection details
Rfree0.2065 1062 5.01 %RANDOM
Rwork0.1846 ---
obs0.1857 21204 100 %-
Displacement parametersBiso max: 87.29 Å2 / Biso mean: 38.08 Å2 / Biso min: 23.54 Å2
Baniso -1Baniso -2Baniso -3
1-1.3932 Å20 Å20 Å2
2--1.3932 Å20 Å2
3----2.7864 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: final / Resolution: 1.81→19.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1033 0 42 94 1169
Biso mean--36.57 53.12 -
Num. residues----131
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d414SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes217HARMONIC5
X-RAY DIFFRACTIONt_it1137HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion149SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies7HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1024SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1137HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg1542HARMONIC20.87
X-RAY DIFFRACTIONt_omega_torsion3.3
X-RAY DIFFRACTIONt_other_torsion14.04
LS refinement shellResolution: 1.81→1.82 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.2332 20 4.71 %
Rwork0.2369 405 -
all0.2368 425 -
obs--99.05 %
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)
12.76840.5638-2.8550.913-0.87583.33270.0732-0.03380.11430.1791-0.0537-0.0465-0.26650.1446-0.0195-0.0008-0.037-0.01240.040.034-0.0389-26.463128.925410.0657
22.6781.32421.93556.6833-1.1852.46590.1337-0.0116-0.0921-0.1850.13820.5753-0.1967-0.3333-0.2718-0.02330.00950.03030.05040.0605-0.0434-43.507821.417519.8971
30.2744-1.1505-0.30793.1624-3.11298.3155-0.00790.02530.02190.32510.15990.3321-0.0801-0.2198-0.1520.0436-0.01360.02590.02110.0357-0.0505-39.745413.371129.9512
43.90551.07530.39974.5818-0.83091.2449-0.06130.2142-0.13590.01490.0386-0.06250.1489-0.01710.02270.0509-0.01480.0043-0.03560.0032-0.0356-32.07258.990718.8931
57.2217-0.34392.20835.43060.5484.58630.1112-0.007-0.4298-0.3470.0727-0.04460.2368-0.4917-0.18390.0918-0.1132-0.0748-0.05120.0423-0.0315-39.22971.436516.4615
61.73461.29932.40272.20770.05625.18370.3792-0.1575-0.08770.1885-0.1550.08330.2401-0.2334-0.22430.0885-0.072-0.0204-0.05080.0439-0.0516-36.21966.267731.0061
70.41210.69720.78822.5119-2.50652.5980.13460.0090.07380.2238-0.0980.0435-0.1551-0.071-0.03660.0571-0.0437-0.0102-0.00130.016-0.037-29.704118.3328.5866
80.0735-0.53213.60663.8686-0.42595.13480.12430.02190.09620.3145-0.2094-0.141-0.188-0.15280.08510.0607-0.1062-0.04840.02440.0095-0.0724-22.142321.733233.0111
90.90151.98920.64443.54661.00281.72120.1968-0.0546-0.24640.1596-0.2274-0.26290.22910.07880.03060.0429-0.014-0.0528-0.02030.0575-0.0154-23.63119.855130.9154
103.84072.13423.06385.5260.51415.4630.01960.2997-0.19920.2177-0.1727-0.74350.05750.18430.1531-0.0336-0.0022-0.0986-0.04340.09110.082-13.636713.501731.2195
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 - 33}A28 - 33
3X-RAY DIFFRACTION3{A|34 - 46}A34 - 46
4X-RAY DIFFRACTION4{A|47 - 61}A47 - 61
5X-RAY DIFFRACTION5{A|62 - 68}A62 - 68
6X-RAY DIFFRACTION6{A|69 - 79}A69 - 79
7X-RAY DIFFRACTION7{A|80 - 92}A80 - 92
8X-RAY DIFFRACTION8{A|93 - 101}A93 - 101
9X-RAY DIFFRACTION9{A|102 - 114}A102 - 114
10X-RAY DIFFRACTION10{A|115 - 129}A115 - 129

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