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

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Basic information

Entry
Database: PDB / ID: 6too
TitleCrystal structure of human BCL6 BTB domain in complex with compound 11a
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 mononuclear cell proliferation / negative regulation of mast cell cytokine production / regulation of germinal center formation ...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 mononuclear cell proliferation / negative regulation of mast cell cytokine production / regulation of germinal center formation / 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 / erythrocyte development / Rho protein signal transduction / regulation of immune response / 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 / protein localization / 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 / 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 / metal ion binding / nucleus
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-NR8 / B-cell lymphoma 6 protein
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.53 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)15,7516
Polymers15,1932
Non-polymers5584
Water3,351186
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)31,50112
Polymers30,3854
Non-polymers1,1168
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation12_545x,x-y-1,-z+1/61
Unit cell
Length a, b, c (Å)67.775, 67.775, 165.288
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-425-

HOH

DetailsA, [EDO]B:101 12_545, [EDO]A:203, A 12_545, [EDO]B:101, [EDO]A:203 12_545, B, [EDO]A:202

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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-NR8 / 2-chloranyl-4-[[1-methyl-3-[(2~{S})-2-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 / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 186 / 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: 3.61 Å3/Da / Density % sol: 65.9 %
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: Mar 7, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.966 Å / Relative weight: 1
ReflectionResolution: 1.53→47.85 Å / Num. obs: 34884 / % possible obs: 100 % / Redundancy: 18 % / Biso Wilson estimate: 21.5 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.135 / Rpim(I) all: 0.033 / Rrim(I) all: 0.139 / Net I/σ(I): 16.6 / Num. measured all: 629463 / Scaling rejects: 47
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
1.53-1.5617.93.0223019616860.6850.7253.1091.6100
8.38-47.8514.10.06739952830.9970.0170.06945.899.5

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimless0.7.4data scaling
PHASERphasing
BUSTER2.10.3refinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3BIM

3bim


Resolution: 1.53→47.85 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.952 / SU R Cruickshank DPI: 0.059 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.066 / SU Rfree Blow DPI: 0.065 / SU Rfree Cruickshank DPI: 0.06
RfactorNum. reflection% reflectionSelection details
Rfree0.195 1750 5.03 %RANDOM
Rwork0.176 ---
obs0.177 34785 99.9 %-
Displacement parametersBiso max: 98.88 Å2 / Biso mean: 28.55 Å2 / Biso min: 11.81 Å2
Baniso -1Baniso -2Baniso -3
1--0.9775 Å20 Å20 Å2
2---0.9775 Å20 Å2
3---1.955 Å2
Refine analyzeLuzzati coordinate error obs: 0.19 Å
Refinement stepCycle: final / Resolution: 1.53→47.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1024 0 43 192 1259
Biso mean--25.56 46.92 -
Num. residues----131
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d451SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes240HARMONIC5
X-RAY DIFFRACTIONt_it1245HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion165SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies21HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1674SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1245HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg1707HARMONIC20.95
X-RAY DIFFRACTIONt_omega_torsion3.34
X-RAY DIFFRACTIONt_other_torsion13.67
LS refinement shellResolution: 1.53→1.54 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2848 35 5.03 %
Rwork0.3023 661 -
all0.3016 696 -
obs--99.56 %
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)
13.74720.33752.68161.16561.17616.27640.08840.0769-0.16060.1957-0.07460.04070.3904-0.3598-0.0137-0.0569-0.0320.0019-0.0341-0.0288-0.097828.5213-28.022711.8788
21.15580.5620.20471.48150.06351.51410.1678-0.08780.10090.1890.1624-0.4639-0.05690.3813-0.33020.0959-0.0156-0.04620.1139-0.06070.062941.5119-15.425827.1074
30.96920.29571.88142.1891.47111.11820.0299-0.19140.14880.32440.173-0.1628-0.11410.1755-0.2029-0.0571-0.0156-0.0338-0.0645-0.0522-0.139539.7887-15.851429.0363
41.51161.073-0.30152.99121.21712.18980.1168-0.0120.12790.08180.0498-0.0419-0.230.0376-0.16660.0103-0.03060.0349-0.0626-0.0181-0.044933.6347-9.946324.1523
53.54411.73490.32791.7183-2.27950.78370.1016-0.2426-0.1270.3376-0.23140.15680.08580.15880.12980.105-0.0970.059-0.0153-0.0075-0.046422.5875-23.268431.7036
62.18321.9158-0.83175.1418-0.44385.28780.2541-0.16650.30.4565-0.2460.4264-0.0155-0.4011-0.00810.0131-0.04510.075-0.0649-0.0434-0.047823.4248-10.379930.6497
77.86170.4173-2.82538.1356-0.34810.1332-0.08160.18690.19840.3563-0.22920.7430.1184-0.22450.31080.0111-0.07350.10930.0187-0.09710.082313.7673-14.716130.4753
82.31462.1223-0.42562.37920.83390.07390.1279-0.05930.02190.0382-0.01430.04480.10180.1315-0.1136-0.0745-0.0283-0.02030.1124-0.0773-0.042919.3965-32.52812.1735
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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