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- PDB-6toi: Crystal structure of human BCL6 BTB domain in complex with compou... -

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Basic information

Entry
Database: PDB / ID: 6toi
TitleCrystal structure of human BCL6 BTB domain in complex with compound 11f
Components
  • ALA-TRP-VAL-ILE-PRO-ALA
  • B-cell lymphoma 6 protein
KeywordsTRANSCRIPTION / Cancer / Lymphoma / Inhibitor / Degrader
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 / regulation of cell differentiation / B cell proliferation / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / 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 / DNA-binding transcription repressor activity, RNA polymerase II-specific / cell morphogenesis / heterochromatin formation / negative regulation of cell growth / chromatin DNA binding / sequence-specific double-stranded DNA binding / protein localization / regulation of inflammatory response / regulation of cell population proliferation / actin cytoskeleton organization / DNA-binding transcription factor binding / spermatogenesis / Interleukin-4 and Interleukin-13 signaling / sequence-specific DNA binding / transcription by RNA polymerase II / inflammatory response / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / positive regulation of apoptotic process / negative regulation of DNA-templated transcription / chromatin binding / DNA damage response / nucleolus / negative regulation of transcription by RNA polymerase II / Golgi apparatus / nucleoplasm / identical protein binding / nucleus / metal ion binding
Similarity search - Function
Potassium Channel Kv1.1; Chain A / Potassium Channel Kv1.1; Chain A / 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 ...Potassium Channel Kv1.1; Chain A / Potassium Channel Kv1.1; Chain A / 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 / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-NQN / B-cell lymphoma 6 protein
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.58 Å
AuthorsCollie, G.W. / Rodrigues, 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: 2020
Title: AchievingIn VivoTarget Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders.
Authors: Bellenie, B.R. / Cheung, K.J. / Varela, A. / Pierrat, O.A. / Collie, G.W. / Box, G.M. / Bright, M.D. / Gowan, S. / Hayes, A. / Rodrigues, M.J. / Shetty, K.N. / Carter, M. / Davis, O.A. / ...Authors: Bellenie, B.R. / Cheung, K.J. / Varela, A. / Pierrat, O.A. / Collie, G.W. / Box, G.M. / Bright, M.D. / Gowan, S. / Hayes, A. / Rodrigues, M.J. / Shetty, K.N. / Carter, M. / Davis, O.A. / Henley, A.T. / Innocenti, P. / Johnson, L.D. / Liu, M. / de Klerk, S. / Le Bihan, Y.V. / Lloyd, M.G. / McAndrew, P.C. / Shehu, E. / Talbot, R. / Woodward, H.L. / Burke, R. / Kirkin, V. / van Montfort, R.L.M. / Raynaud, F.I. / Rossanese, O.W. / Hoelder, S.
History
DepositionDec 11, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 22, 2020Provider: repository / Type: Initial release
Revision 1.1May 6, 2020Group: 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 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)16,03110
Polymers15,1932
Non-polymers8388
Water2,810156
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)32,06220
Polymers30,3854
Non-polymers1,67716
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation12_545x,x-y-1,-z+1/61
Buried area7250 Å2
ΔGint-32 kcal/mol
Surface area13860 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.660, 67.660, 166.640
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-310-

HOH

21A-372-

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 , 4 types, 164 molecules

#3: Chemical ChemComp-NQN / 2-chloranyl-4-[[1-methyl-3-[(3~{R})-3-oxidanylbutyl]-2-oxidanylidene-benzimidazol-5-yl]amino]pyridine-3-carbonitrile


Mass: 371.821 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H18ClN5O2 / 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: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 156 / 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

CrystalDensity Matthews: 3.62 Å3/Da / Density % sol: 66.06 %
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: Aug 27, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.966 Å / Relative weight: 1
ReflectionResolution: 1.58→55.278 Å / Num. obs: 31728 / % possible obs: 99.9 % / Redundancy: 12.4 % / Biso Wilson estimate: 22.06 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.091 / Rpim(I) all: 0.027 / Rrim(I) all: 0.096 / Net I/σ(I): 16.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
1.58-1.60811.90.76915560.3520.2310.80799.5
4.291-55.27810.70.03917730.9990.0130.04198.6

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Phasing

PhasingMethod: molecular replacement

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Processing

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

3bim


Resolution: 1.58→20.57 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.956 / SU R Cruickshank DPI: 0.058 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.063 / SU Rfree Blow DPI: 0.064 / SU Rfree Cruickshank DPI: 0.059
RfactorNum. reflection% reflectionSelection details
Rfree0.184 1539 4.85 %RANDOM
Rwork0.163 ---
obs0.164 31707 99.9 %-
Displacement parametersBiso max: 90.77 Å2 / Biso mean: 29.54 Å2 / Biso min: 3.79 Å2
Baniso -1Baniso -2Baniso -3
1-1.1047 Å20 Å20 Å2
2--1.1047 Å20 Å2
3----2.2093 Å2
Refine analyzeLuzzati coordinate error obs: 0.2 Å
Refinement stepCycle: final / Resolution: 1.58→20.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1014 0 54 163 1231
Biso mean--35.85 47.17 -
Num. residues----131
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d419SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes224HARMONIC5
X-RAY DIFFRACTIONt_it1197HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion160SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies18HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1610SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1197HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg1626HARMONIC21.03
X-RAY DIFFRACTIONt_omega_torsion3.7
X-RAY DIFFRACTIONt_other_torsion14.08
LS refinement shellResolution: 1.58→1.59 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2815 33 5.2 %
Rwork0.2674 602 -
all0.2682 635 -
obs--98.58 %
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)
13.96180.48162.67371.67761.18985.72410.04930.007-0.10690.1623-0.05740.01910.2705-0.330.0081-0.0287-0.01960.0078-0.0149-0.0198-0.115828.37-27.805711.6368
20.51250.14670.94353.90690.43182.88650.1449-0.03850.07110.27880.0749-0.4096-0.18670.1906-0.21980.2048-0.0342-0.04870.2271-0.04070.118441.1968-15.283527.8614
30.81650.29941.36790.79980.75651.4599-0.0738-0.16940.01280.42370.0848-0.0511-0.15140.1913-0.011-0.1511-0.0096-0.0478-0.1939-0.0272-0.30439.6643-15.980928.5244
41.28711.2558-0.12752.94710.94542.07520.1027-0.00290.08260.1130.0008-0.0624-0.19970.0629-0.10350.0269-0.02830.0187-0.0328-0.0127-0.08133.2622-10.478424.1227
51.95351.2632-0.55411.6664-1.4451.47350.1012-0.2956-0.00950.3356-0.2160.18840.02790.18420.11470.155-0.09290.05240.0657-0.0107-0.060522.3282-22.755432.5993
63.74053.4597-0.99146.4669-0.88665.48830.2516-0.20580.32930.4967-0.27480.4081-0.262-0.32660.02320.0123-0.03250.0657-0.0601-0.0552-0.087923.4197-10.515831.0151
77.77750.2929-1.85428.60560.25830.0164-0.06930.08390.20770.4382-0.1820.72870.1889-0.4140.25120.0261-0.05790.09560.0595-0.10260.02313.6496-15.02331.2656
82.64020.94671.13870.67173.69421.15910.0967-0.05-0.0477-0.0990.05720.0750.0747-0.0494-0.1539-0.0596-0.0519-0.01320.128-0.0315-0.065919.2167-32.51482.1249
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 - 92}A47 - 92
5X-RAY DIFFRACTION5{A|93 - 101}A93 - 101
6X-RAY DIFFRACTION6{A|102 - 114}A102 - 114
7X-RAY DIFFRACTION7{A|115 - 129}A115 - 129
8X-RAY DIFFRACTION8{B|0 - 5}B0 - 5

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