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- PDB-5eis: FIRST DOMAIN OF HUMAN BROMODOMAIN BRD4 IN COMPLEX WITH INHIBITOR ... -

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Basic information

Entry
Database: PDB / ID: 5eis
TitleFIRST DOMAIN OF HUMAN BROMODOMAIN BRD4 IN COMPLEX WITH INHIBITOR 3-(4-Chlorobenzyl)-7-ethyl-3,7-dihydropurine-2,6-dione
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION / INHIBITOR / HISTONE / EPIGENETIC READER / BROMODOMAIN / BRD4_BD1
Function / homology
Function and homology information


RNA polymerase II C-terminal domain binding / P-TEFb complex binding / negative regulation of DNA damage checkpoint / histone H4 reader activity / host-mediated suppression of viral transcription / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of T-helper 17 cell lineage commitment / : / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome ...RNA polymerase II C-terminal domain binding / P-TEFb complex binding / negative regulation of DNA damage checkpoint / histone H4 reader activity / host-mediated suppression of viral transcription / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of T-helper 17 cell lineage commitment / : / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / transcription coregulator activity / positive regulation of transcription elongation by RNA polymerase II / p53 binding / chromosome / regulation of inflammatory response / histone binding / Potential therapeutics for SARS / transcription coactivator activity / positive regulation of canonical NF-kappaB signal transduction / transcription cis-regulatory region binding / chromatin remodeling / protein serine/threonine kinase activity / DNA damage response / chromatin binding / regulation of transcription by RNA polymerase II / chromatin / 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 I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain-like ...Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain-like / Histone Acetyltransferase; Chain A / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-5OU / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsRaux, B. / Rebuffet, E. / Betzi, S. / Morelli, X.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Exploring Selective Inhibition of the First Bromodomain of the Human Bromodomain and Extra-terminal Domain (BET) Proteins.
Authors: Raux, B. / Voitovich, Y. / Derviaux, C. / Lugari, A. / Rebuffet, E. / Milhas, S. / Priet, S. / Roux, T. / Trinquet, E. / Guillemot, J.C. / Knapp, S. / Brunel, J.M. / Fedorov, A.Y. / ...Authors: Raux, B. / Voitovich, Y. / Derviaux, C. / Lugari, A. / Rebuffet, E. / Milhas, S. / Priet, S. / Roux, T. / Trinquet, E. / Guillemot, J.C. / Knapp, S. / Brunel, J.M. / Fedorov, A.Y. / Collette, Y. / Roche, P. / Betzi, S. / Combes, S. / Morelli, X.
History
DepositionOct 30, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jan 20, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 9, 2016Group: Database references
Revision 1.2Jan 10, 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

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,5284
Polymers15,0991
Non-polymers4293
Water1,874104
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area330 Å2
ΔGint4 kcal/mol
Surface area7450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)35.935, 46.545, 77.658
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 15099.380 Da / Num. of mol.: 1 / Fragment: N-TERMINAL BROMODOMAIN, RESIDUES 44-168 / Mutation: NO
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: pDEST17 / Production host: Escherichia coli (E. coli) / References: UniProt: O60885
#2: Chemical ChemComp-5OU / 3-[(4-chlorophenyl)methyl]-7-ethyl-purine-2,6-dione


Mass: 304.732 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H13ClN4O2
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / PROTEIN HUNK1 / BRD4 / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Fragment: N-TERMINAL BROMODOMAIN, RESIDUES 42-168 / Mutation: NO
Source method: isolated from a genetically manipulated source
Formula: C2H6O2 / Source: (gene. exp.) Homo sapiens (human) / Gene: 19p13.12 / Plasmid: pDEST17 / Production host: Escherichia coli (E. coli)
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 104 / Source method: isolated from a natural source / Formula: H2O

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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: 42.9 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop
Details: ratio 1:1 (protein:precipitant). 16 mg/mL Brd4_BD1 protein. 2.5 mM inhibitor (in DMSO) final concentration. Protein buffer: 0.1M HEPES (pH 7.5) 0.15 mM NaCl. Precipitant agent: 19% (w/v) PEG ...Details: ratio 1:1 (protein:precipitant). 16 mg/mL Brd4_BD1 protein. 2.5 mM inhibitor (in DMSO) final concentration. Protein buffer: 0.1M HEPES (pH 7.5) 0.15 mM NaCl. Precipitant agent: 19% (w/v) PEG 3350, 0.25M ammonium sulfate, 0.1M Tris pH 8.5. Cryoprotectant: 10% (w/v) ethylene glycol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.8726 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: May 15, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8726 Å / Relative weight: 1
ReflectionResolution: 1.6→50 Å / Num. obs: 17766 / % possible obs: 99.4 % / Redundancy: 4.6 % / Rmerge(I) obs: 0.054 / Net I/σ(I): 14.87
Reflection shellResolution: 1.6→1.7 Å / Redundancy: 4.7 % / Rmerge(I) obs: 0.558 / Mean I/σ(I) obs: 2.73 / % possible all: 98.7

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Processing

Software
NameVersionClassification
XDSOct 15, 2015;data reduction
XDSOct 15, 2015;data scaling
PHASER2.5.7phasing
REFMAC5.8.0135refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OSS

2oss


Resolution: 1.6→39.92 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.954 / SU B: 2.975 / SU ML: 0.094 / Cross valid method: THROUGHOUT / ESU R: 0.094 / ESU R Free: 0.095 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2191 889 5 %RANDOM
Rwork0.18269 ---
obs0.18448 16876 99.41 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 27.433 Å2
Baniso -1Baniso -2Baniso -3
1-4.27 Å20 Å20 Å2
2---1.48 Å20 Å2
3----2.79 Å2
Refinement stepCycle: LAST / Resolution: 1.6→39.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1062 0 29 104 1195
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.021131
X-RAY DIFFRACTIONr_bond_other_d0.0030.021072
X-RAY DIFFRACTIONr_angle_refined_deg1.8591.9981538
X-RAY DIFFRACTIONr_angle_other_deg1.0643.0032479
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2765128
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.2022655
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.35215199
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.966153
X-RAY DIFFRACTIONr_chiral_restr0.1070.2159
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0211263
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02253
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.5182.448512
X-RAY DIFFRACTIONr_mcbond_other2.4652.435511
X-RAY DIFFRACTIONr_mcangle_it3.5373.644640
X-RAY DIFFRACTIONr_mcangle_other3.5533.657641
X-RAY DIFFRACTIONr_scbond_it3.4132.766619
X-RAY DIFFRACTIONr_scbond_other3.4132.766619
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.7684.003899
X-RAY DIFFRACTIONr_long_range_B_refined6.37720.4711407
X-RAY DIFFRACTIONr_long_range_B_other6.37920.4861408
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.599→1.64 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.364 63 -
Rwork0.341 1196 -
obs--97.07 %

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