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- PDB-8c78: Crystal structure of human BCL6 BTB domain in complex with compou... -

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Basic information

Entry
Database: PDB / ID: 8c78
TitleCrystal structure of human BCL6 BTB domain in complex with compound CCT374705
ComponentsB-cell lymphoma 6 protein
KeywordsTRANSCRIPTION / Inhibitor / Cancer / Lymphoma
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-TWI / B-cell lymphoma 6 protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.8 Å
AuthorsLe 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: 2023
Title: Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones.
Authors: Harnden, A.C. / Davis, O.A. / Box, G.M. / Hayes, A. / Johnson, L.D. / Henley, A.T. / de Haven Brandon, A.K. / Valenti, M. / Cheung, K.J. / Brennan, A. / Huckvale, R. / Pierrat, O.A. / ...Authors: Harnden, A.C. / Davis, O.A. / Box, G.M. / Hayes, A. / Johnson, L.D. / Henley, A.T. / de Haven Brandon, A.K. / Valenti, M. / Cheung, K.J. / Brennan, A. / Huckvale, R. / Pierrat, O.A. / Talbot, R. / Bright, M.D. / Akpinar, H.A. / Miller, D.S.J. / Tarantino, D. / Gowan, S. / de Klerk, S. / McAndrew, P.C. / Le Bihan, Y.V. / Meniconi, M. / Burke, R. / Kirkin, V. / van Montfort, R.L.M. / Raynaud, F.I. / Rossanese, O.W. / Bellenie, B.R. / Hoelder, S.
History
DepositionJan 13, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 26, 2023Provider: repository / Type: Initial release
Revision 1.1May 10, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 2.0May 24, 2023Group: Non-polymer description / Category: chem_comp / Item: _chem_comp.formula
Revision 2.1Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)17,2698
Polymers16,4991
Non-polymers7707
Water2,702150
1
A: B-cell lymphoma 6 protein
hetero molecules

A: B-cell lymphoma 6 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,53816
Polymers32,9982
Non-polymers1,54014
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation12_565x,x-y+1,-z+1/61
Buried area5400 Å2
ΔGint-53 kcal/mol
Surface area13620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.588, 67.588, 167.162
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-324-

HOH

21A-358-

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-TWI / (2~{S})-10-[(3-chloranyl-2-fluoranyl-pyridin-4-yl)amino]-2-cyclopropyl-3,3-bis(fluoranyl)-7-methyl-2,4-dihydro-1~{H}-[1,4]oxazepino[2,3-c]quinolin-6-one


Mass: 450.841 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H18ClF3N4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-CL / CHLORIDE ION


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


Mass: 18.015 Da / Num. of mol.: 150 / 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: 3.34 Å3/Da / Density % sol: 63.18 %
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: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: May 5, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.8→47.95 Å / Num. obs: 21872 / % possible obs: 100 % / Redundancy: 25.4 % / Biso Wilson estimate: 40.39 Å2 / CC1/2: 0.988 / Rmerge(I) obs: 0.074 / Rpim(I) all: 0.015 / Rrim(I) all: 0.076 / Net I/σ(I): 24.3 / Num. measured all: 554891 / Scaling rejects: 786
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
1.8-1.8428.12.593543212620.7250.4942.6371.299.7
9-47.9521.20.02251502430.9380.0060.023122.899.5

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
Aimless0.7.7data scaling
PHASERphasing
BUSTER2.10.4 (3-FEB-2022)refinement
PDB_EXTRACT3.24data extraction
DIALSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→47.95 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.95 / SU R Cruickshank DPI: 0.099 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.111 / SU Rfree Blow DPI: 0.109 / SU Rfree Cruickshank DPI: 0.101
RfactorNum. reflection% reflectionSelection details
Rfree0.2321 1034 4.74 %RANDOM
Rwork0.1988 ---
obs0.2004 21793 100 %-
Displacement parametersBiso max: 91.34 Å2 / Biso mean: 44.73 Å2 / Biso min: 28.22 Å2
Baniso -1Baniso -2Baniso -3
1--2.352 Å20 Å20 Å2
2---2.352 Å20 Å2
3---4.704 Å2
Refine analyzeLuzzati coordinate error obs: 0.22 Å
Refinement stepCycle: final / Resolution: 1.8→47.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1023 0 49 154 1226
Biso mean--45.86 59.52 -
Num. residues----130
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d412SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes223HARMONIC5
X-RAY DIFFRACTIONt_it1155HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion152SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies12HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1150SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1155HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg1574HARMONIC20.9
X-RAY DIFFRACTIONt_omega_torsion3.25
X-RAY DIFFRACTIONt_other_torsion15.32
LS refinement shellResolution: 1.8→1.81 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.2697 24 5.5 %
Rwork0.2725 412 -
all0.2724 436 -
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)
16.24493.0035-2.26384.12281.17470.0629-0.08760.31740.2926-0.10990.061-0.1011-0.13340.28920.0267-0.0841-0.02640.00130.13310.0951-0.043-19.16630.17362.3832
20.49380.05780.11341.8171-1.38332.10.0528-0.04860.09340.23340.05450.1496-0.1768-0.1403-0.10730.02290.01220.0272-0.00440.0199-0.0086-36.866922.233121.506
30.48790.25420.49152.4723-1.8572.7390.0912-0.02930.07250.1527-0.050.210.0476-0.1133-0.04120.0303-0.04210.03760.02080.0201-0.0089-39.379616.682127.9099
43.73511.0326-0.70853.1564-1.10560.2142-0.07060.1523-0.10840.0335-0.0037-0.06670.1457-0.00180.07430.0566-0.0214-0.0187-0.0467-0.00180.0129-31.54869.598419.1244
53.28063.2583-0.70215.2082.95534.36260.1860.0849-0.29-0.438-0.25350.06250.2417-0.48890.06750.044-0.1172-0.0915-0.03950.033-0.018-39.7533.18517.7345
64.4981.63892.25522.0111.1242.72660.0973-0.1377-0.03960.5471-0.17190.30170.1414-0.12840.07460.1491-0.119-0.0172-0.06450.0638-0.0721-34.45677.063633.0087
70.8850.96330.55462.1841-2.4712.79030.2768-0.03990.14130.3017-0.23540.009-0.1261-0.0583-0.04140.0891-0.0663-0.0214-0.02610.0052-0.0167-29.322419.097928.6671
81.11610.06240.44120.71220.40762.53870.2303-0.08460.33290.3097-0.3292-0.4363-0.2447-0.27450.09890.1381-0.1359-0.1199-0.04530.0202-0.0414-21.846222.647732.6015
91.04671.68470.95331.60080.55812.94330.351-0.063-0.36410.2535-0.402-0.32950.1255-0.05110.0510.0848-0.059-0.1104-0.04790.10530.0023-23.319910.68531.1831
103.55322.10943.26085.84230.16321.1555-0.07840.3736-0.09190.31140.0196-0.5219-0.1273-0.02630.05880.0024-0.0063-0.1511-0.06850.08820.0879-13.425914.782531.8396
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|0 - 13}A0 - 13
2X-RAY DIFFRACTION2{A|14 - 40}A14 - 40
3X-RAY DIFFRACTION3{A|41 - 46}A41 - 46
4X-RAY DIFFRACTION4{A|47 - 61}A47 - 61
5X-RAY DIFFRACTION5{A|62 - 70}A62 - 70
6X-RAY DIFFRACTION6{A|71 - 79}A71 - 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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