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- PDB-8p9l: Crystal structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 8p9l
TitleCrystal structure of the first bromodomain of human BRD4 in complex with the dual BET/HDAC inhibitor NB512
ComponentsBromodomain-containing protein 4
KeywordsGENE REGULATION / bromodomain / epigenetic drugs / inhibitor / cancer therapy
Function / homology
Function and homology information


RNA polymerase II C-terminal domain binding / negative regulation of DNA damage checkpoint / P-TEFb complex binding / negative regulation by host of viral transcription / positive regulation of T-helper 17 cell lineage commitment / positive regulation of G2/M transition of mitotic cell cycle / histone reader activity / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / positive regulation of transcription elongation by RNA polymerase II ...RNA polymerase II C-terminal domain binding / negative regulation of DNA damage checkpoint / P-TEFb complex binding / negative regulation by host of viral transcription / positive regulation of T-helper 17 cell lineage commitment / positive regulation of G2/M transition of mitotic cell cycle / histone reader activity / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / positive regulation of transcription elongation by RNA polymerase II / transcription coregulator activity / lysine-acetylated histone binding / p53 binding / chromosome / regulation of inflammatory response / positive regulation of canonical NF-kappaB signal transduction / Potential therapeutics for SARS / transcription coactivator activity / transcription cis-regulatory region binding / chromatin remodeling / DNA damage response / chromatin binding / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / enzyme binding / positive regulation of transcription by RNA polymerase II / nucleoplasm / nucleus
Similarity search - Function
Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain, conserved site ...Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily
Similarity search - Domain/homology
Chem-XA3 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.29 Å
AuthorsBalourdas, D.I. / Bauer, N. / Knapp, S. / Joerger, A.C. / Structural Genomics Consortium (SGC)
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation (DFG)JO 1473/1-3 Germany
CitationJournal: Acs Chem.Biol. / Year: 2024
Title: Development of Potent Dual BET/HDAC Inhibitors via Pharmacophore Merging and Structure-Guided Optimization.
Authors: Bauer, N. / Balourdas, D.I. / Schneider, J.R. / Zhang, X. / Berger, L.M. / Berger, B.T. / Schwalm, M.P. / Klopp, N.A. / Siveke, J.T. / Knapp, S. / Joerger, A.C.
History
DepositionJun 6, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 5, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond
Revision 1.2Jun 26, 2024Group: 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,7836
Polymers15,0991
Non-polymers6845
Water2,180121
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.232, 52.397, 54.984
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Bromodomain-containing protein 4 / Protein HUNK1


Mass: 15099.380 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Production host: Escherichia coli (E. coli) / References: UniProt: O60885
#2: Chemical ChemComp-XA3 / ~{N}-(2-azanyl-5-phenyl-phenyl)-5-(6-methyl-7-oxidanylidene-1~{H}-pyrrolo[2,3-c]pyridin-4-yl)pyridine-2-carboxamide


Mass: 435.477 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H21N5O2 / 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: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 121 / 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: 2.05 Å3/Da / Density % sol: 39.99 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: Protein solution: 10 mg/mL in 25 mM HEPES pH 7.5, 150 mM NaCl, 0.5 mM TCEP, 5% glycerol, 1 mM inhibitor NB512. Reservoir buffer: 24% PEG 3350, 0.1 M Na/K Tartrate, 10% ethylene glycol, 0.1 M ...Details: Protein solution: 10 mg/mL in 25 mM HEPES pH 7.5, 150 mM NaCl, 0.5 mM TCEP, 5% glycerol, 1 mM inhibitor NB512. Reservoir buffer: 24% PEG 3350, 0.1 M Na/K Tartrate, 10% ethylene glycol, 0.1 M bis-tris propane pH 7.3. Vol ratio 1:2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 15, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.29→42.2 Å / Num. obs: 31310 / % possible obs: 99.7 % / Redundancy: 8.6 % / Biso Wilson estimate: 19.99 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.027 / Net I/σ(I): 31.8
Reflection shellResolution: 1.29→1.31 Å / Rmerge(I) obs: 1.005 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 1525 / CC1/2: 0.876

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.29→37.93 Å / SU ML: 0.144 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 18.6686
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1881 1479 4.73 %
Rwork0.1632 29758 -
obs0.1643 31237 99.51 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 26.77 Å2
Refinement stepCycle: LAST / Resolution: 1.29→37.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1014 0 49 121 1184
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00551109
X-RAY DIFFRACTIONf_angle_d0.83341513
X-RAY DIFFRACTIONf_chiral_restr0.0732158
X-RAY DIFFRACTIONf_plane_restr0.0076226
X-RAY DIFFRACTIONf_dihedral_angle_d4.6089175
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.29-1.330.30791320.3022661X-RAY DIFFRACTION99.25
1.33-1.380.2341550.21582638X-RAY DIFFRACTION99.36
1.38-1.430.22351380.19152648X-RAY DIFFRACTION99.71
1.43-1.50.21811650.18962641X-RAY DIFFRACTION99.54
1.5-1.580.20971290.14862698X-RAY DIFFRACTION99.79
1.58-1.680.17881200.13912701X-RAY DIFFRACTION99.86
1.68-1.810.1761320.14732692X-RAY DIFFRACTION99.44
1.81-1.990.1921290.15092690X-RAY DIFFRACTION99.26
1.99-2.280.17281100.152765X-RAY DIFFRACTION100
2.28-2.870.19481250.16582769X-RAY DIFFRACTION99.9
2.87-37.930.17931440.16632855X-RAY DIFFRACTION98.55

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