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- PDB-7zwo: Crystal structure of human BCL6 BTB domain in complex with compound 2 -

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Basic information

Entry
Database: PDB / ID: 7zwo
TitleCrystal structure of human BCL6 BTB domain in complex with compound 2
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 / regulation of cell differentiation / regulation of T cell proliferation / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / B cell proliferation / negative regulation of cellular senescence / negative regulation of cell-matrix adhesion / negative regulation of Notch signaling pathway / Rho protein signal transduction / regulation of immune response / erythrocyte development / 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 / cell morphogenesis / chromatin DNA binding / DNA-binding transcription repressor activity, RNA polymerase II-specific / 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 / DNA-binding transcription factor binding / spermatogenesis / sequence-specific DNA binding / transcription by RNA polymerase II / positive regulation of apoptotic process / inflammatory response / 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 / 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-KCB / B-cell lymphoma 6 protein
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.39 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)15,9048
Polymers15,1932
Non-polymers7116
Water3,495194
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)31,80816
Polymers30,3854
Non-polymers1,42212
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation12_535x,x-y-2,-z+1/61
Buried area6570 Å2
ΔGint-32 kcal/mol
Surface area14230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.190, 67.190, 165.735
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122

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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: 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)
#3: Chemical ChemComp-KCB / (5~{S},7~{R})-5-(4-chlorophenyl)-7-(2,3,4-trimethoxyphenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine


Mass: 400.859 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H21ClN4O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 194 / 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

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: Jul 27, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.966 Å / Relative weight: 1
ReflectionResolution: 1.39→47.62 Å / Num. obs: 45535 / % possible obs: 100 % / Redundancy: 18.8 % / Biso Wilson estimate: 19.25 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.126 / Rpim(I) all: 0.03 / Rrim(I) all: 0.13 / Net I/σ(I): 14.5 / Num. measured all: 858182
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
1.39-1.4419.32.3738453443740.5580.552.4371.5100
5.38-47.6216.10.055154549600.9990.0140.05643.799.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
BUSTER2.10.3refinement
XDSdata reduction
Aimless0.5.27data scaling
PHASERphasing
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3BIM

3bim


Resolution: 1.39→20.03 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.957 / SU R Cruickshank DPI: 0.042 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.047 / SU Rfree Blow DPI: 0.048 / SU Rfree Cruickshank DPI: 0.043
RfactorNum. reflection% reflectionSelection details
Rfree0.183 2316 5.1 %RANDOM
Rwork0.167 ---
obs0.168 45413 100 %-
Displacement parametersBiso max: 104.64 Å2 / Biso mean: 25.1 Å2 / Biso min: 11.72 Å2
Baniso -1Baniso -2Baniso -3
1--1.4046 Å20 Å20 Å2
2---1.4046 Å20 Å2
3---2.8093 Å2
Refine analyzeLuzzati coordinate error obs: 0.17 Å
Refinement stepCycle: final / Resolution: 1.39→20.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1018 0 48 200 1266
Biso mean--33.42 44.49 -
Num. residues----131
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d417SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes219HARMONIC5
X-RAY DIFFRACTIONt_it1163HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion156SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies13HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1629SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1163HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg1580HARMONIC21.03
X-RAY DIFFRACTIONt_omega_torsion3.67
X-RAY DIFFRACTIONt_other_torsion12.98
LS refinement shellResolution: 1.39→1.4 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2659 37 4.07 %
Rwork0.2512 872 -
all0.2518 909 -
obs--99.89 %
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)
11.1370.48310.53810.83480.78852.18990.0396-0.0702-0.01340.0669-0.0151-0.020.1556-0.1502-0.0245-0.031-0.0071-0.0014-0.0218-0.0113-0.003999.1013-26.297514.0482
21.0242-0.24692.68891.8107-1.80822.892-0.1219-0.20920.03260.30590.1382-0.2275-0.00320.1003-0.01640.0906-0.0031-0.01510.0523-0.02950.0626106.6816-10.700631.9107
31.1919-0.29681.40830.85971.32621.6665-0.0393-0.10620.02210.26880.0935-0.05660.05610.1318-0.0542-0.0757-0.0038-0.0092-0.097-0.0239-0.0874106.9152-15.921127.8291
41.82611.0695-0.3372.16980.63271.77140.05630.09850.09-0.1934-0.00420.0017-0.2367-0.0207-0.05210.0321-0.00660.0149-0.0324-0.00250.016101.2105-6.771917.9233
50.76220.5767-0.31761.4510.0350.99360.0992-0.0664-0.0180.1789-0.0769-0.032-0.0157-0.0779-0.0223-0.0101-0.02670.0099-0.0305-0.014-0.009396.5556-16.043530.2408
63.64192.9563-2.49084.2659-1.50662.13080.06880.08470.33820.1688-0.01370.4298-0.0406-0.2594-0.0551-0.0252-0.01840.0429-0.0012-0.03390.049985.284-12.361331.0823
78.14132.35940.3510.01061.33212.05930.1217-0.08410.01390.04230.03180.05490.051-0.0338-0.1535-0.0395-0.0272-0.00340.0306-0.03310.01586.5183-31.4482.3578
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|5 - 33}A5 - 33
2X-RAY DIFFRACTION2{A|34 - 40}A34 - 40
3X-RAY DIFFRACTION3{A|41 - 46}A41 - 46
4X-RAY DIFFRACTION4{A|47 - 68}A47 - 68
5X-RAY DIFFRACTION5{A|69 - 101}A69 - 101
6X-RAY DIFFRACTION6{A|102 - 129}A102 - 129
7X-RAY DIFFRACTION7{B|0 - 5}B0 - 5

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