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- PDB-7lwg: Crystal structure of the BCL6 BTB domain in complex with OICR-12694 -

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Basic information

Entry
Database: PDB / ID: 7lwg
TitleCrystal structure of the BCL6 BTB domain in complex with OICR-12694
ComponentsB-cell lymphoma 6 protein
KeywordsTRANSCRIPTION/INHIBITOR / immunity / inflammatory response / transcription repressor / TRANSCRIPTION-INHIBITOR complex
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-YN7 / B-cell lymphoma 6 protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.3 Å
AuthorsKuntz, D.A. / Prive, G.G.
CitationJournal: Acs Med.Chem.Lett. / Year: 2023
Title: Discovery of OICR12694: A Novel, Potent, Selective, and Orally Bioavailable BCL6 BTB Inhibitor.
Authors: Mamai, A. / Chau, A.M. / Wilson, B.J. / Watson, I.D. / Joseph, B.B. / Subramanian, P.R. / Morshed, M.M. / Morin, J.A. / Prakesch, M.A. / Lu, T. / Connolly, P. / Kuntz, D.A. / Pomroy, N.C. / ...Authors: Mamai, A. / Chau, A.M. / Wilson, B.J. / Watson, I.D. / Joseph, B.B. / Subramanian, P.R. / Morshed, M.M. / Morin, J.A. / Prakesch, M.A. / Lu, T. / Connolly, P. / Kuntz, D.A. / Pomroy, N.C. / Poda, G. / Nguyen, K. / Marcellus, R. / Strathdee, G. / Theriault, B. / Subramaniam, R. / Mohammed, M. / Abibi, A. / Chan, M. / Winston, J. / Kiyota, T. / Undzys, E. / Aman, A. / Austin, N. / Du Jardin, M. / Packman, K. / Phillippar, U. / Attar, R. / Edwards, J. / O'Meara, J. / Uehling, D.E. / Al-Awar, R. / Prive, G.G. / Isaac, M.B.
History
DepositionMar 1, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 9, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 25, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Mar 1, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.3Oct 25, 2023Group: 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: B-cell lymphoma 6 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,37810
Polymers28,8312
Non-polymers1,5468
Water3,837213
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: homology, btb poz domains are known to form domain swapped homo dimers
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4510 Å2
ΔGint-28 kcal/mol
Surface area12530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)31.786, 72.939, 55.336
Angle α, β, γ (deg.)90.00, 106.32, 90.00
Int Tables number4
Space group name H-MP1211
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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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: 14415.693 Da / Num. of mol.: 2 / Fragment: BTB domain, residues 5-129 / Mutation: C8Q, C67R, C84N
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BCL6, BCL5, LAZ3, ZBTB27, ZNF51
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P41182
#2: Chemical ChemComp-YN7 / 5-{(5S)-1-[2-({3-chloro-6-[(2S)-2,4-dimethylpiperazin-1-yl]-2-fluoropyridin-4-yl}amino)-2-oxoethyl]-4-oxo-4,6,7,8-tetrahydro-1H-dipyrrolo[1,2-a:2',3'-d]pyrimidin-3-yl}-3,4-difluoro-2-hydroxybenzamide


Mass: 645.032 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H28ClF3N8O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical
ChemComp-UNX / UNKNOWN ATOM OR ION


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 213 / 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: 2.15 Å3/Da / Density % sol: 42.8 %
Crystal growTemperature: 293 K / Method: microbatch / pH: 5.2
Details: 10% PEG 6000, 0.1M Acetate:MES buffer pH 5.2, 10% DMSO, 50 mM CaCl2 with microseeding

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 26, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.3→53.11 Å / Num. obs: 57693 / % possible obs: 97 % / Redundancy: 4.4 % / Biso Wilson estimate: 10.4 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.066 / Rpim(I) all: 0.035 / Rrim(I) all: 0.075 / Net I/σ(I): 9.4
Reflection shellResolution: 1.3→1.32 Å / Redundancy: 4.2 % / Rmerge(I) obs: 0.432 / Mean I/σ(I) obs: 2.9 / Num. unique obs: 2862 / CC1/2: 0.868 / Rpim(I) all: 0.237 / Rrim(I) all: 0.495 / % possible all: 94.5

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Processing

Software
NameVersionClassification
PHENIX(1.18.2_3874: ???)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3LB7

3lb7
PDB Unreleased entry


Resolution: 1.3→53.11 Å / SU ML: 0.14 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 19.66 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1836 2853 4.99 %
Rwork0.1442 --
obs0.1462 57180 96.11 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.3→53.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1950 0 106 213 2269
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.012177
X-RAY DIFFRACTIONf_angle_d1.2612968
X-RAY DIFFRACTIONf_dihedral_angle_d25.479822
X-RAY DIFFRACTIONf_chiral_restr0.076335
X-RAY DIFFRACTIONf_plane_restr0.007371
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.3-1.320.34031390.26452661X-RAY DIFFRACTION93
1.32-1.350.30961110.23962592X-RAY DIFFRACTION93
1.35-1.370.26211520.21762633X-RAY DIFFRACTION94
1.37-1.40.25561360.20452597X-RAY DIFFRACTION93
1.4-1.430.22691410.19212646X-RAY DIFFRACTION93
1.43-1.460.2331440.17332645X-RAY DIFFRACTION94
1.46-1.50.21611210.15932715X-RAY DIFFRACTION95
1.5-1.540.20441300.15062687X-RAY DIFFRACTION95
1.54-1.590.20921540.13712689X-RAY DIFFRACTION95
1.59-1.640.16721550.12812671X-RAY DIFFRACTION96
1.64-1.70.18181690.12152720X-RAY DIFFRACTION96
1.7-1.760.16311620.11432720X-RAY DIFFRACTION97
1.76-1.840.1451330.11072712X-RAY DIFFRACTION97
1.84-1.940.15751340.10962771X-RAY DIFFRACTION98
1.94-2.060.15681560.11072740X-RAY DIFFRACTION98
2.06-2.220.14911590.10452797X-RAY DIFFRACTION98
2.22-2.450.15061570.11332786X-RAY DIFFRACTION99
2.45-2.80.14871360.12362800X-RAY DIFFRACTION99
2.8-3.530.17861260.14372873X-RAY DIFFRACTION99
3.53-53.110.20551380.17992872X-RAY DIFFRACTION100

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