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- PDB-5ei4: First domain of human bromodomain BRD4 in complex with inhibitor ... -

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Basic information

Entry
Database: PDB / ID: 5ei4
TitleFirst domain of human bromodomain BRD4 in complex with inhibitor 8-(5-Amino-1H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-(4-chlorobenzyl)-7-ethyl-3,7-dihydropurine-2,6-dione
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION / INHIBITOR / HISTONE / EPIGENETIC READER / BROMODOMAIN / BRD4 / Brd4_BD1 / Brd4_BD1 29-O
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 / RNA polymerase II CTD heptapeptide repeat kinase activity / histone reader 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 / RNA polymerase II CTD heptapeptide repeat kinase activity / histone reader 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 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 / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-5NV / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.05 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 29, 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)15,5943
Polymers15,0991
Non-polymers4952
Water2,954164
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area200 Å2
ΔGint3 kcal/mol
Surface area7550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)37.353, 44.069, 78.272
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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: pDEST17 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Star / References: UniProt: O60885
#2: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-5NV / 8-[(3-azanyl-1~{H}-1,2,4-triazol-5-yl)sulfanylmethyl]-3-[(4-chlorophenyl)methyl]-7-ethyl-purine-2,6-dione


Mass: 432.887 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H17ClN8O2S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 164 / 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: 2.14 Å3/Da / Density % sol: 42.44 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: Ratio 1:1 (protein:precipitant). 12 mg/mL BRD4_BD1 protein. 2.5 mM inhibitor (in DMSO) final concentration. Protein buffer: 0.01M HEPES (pH 7.5), 0.15M NaCl. Precipitant agent : 0.3M Na ...Details: Ratio 1:1 (protein:precipitant). 12 mg/mL BRD4_BD1 protein. 2.5 mM inhibitor (in DMSO) final concentration. Protein buffer: 0.01M HEPES (pH 7.5), 0.15M NaCl. Precipitant agent : 0.3M Na Formate, 0.1M NaCl, 22% PEG3350, 10% ethylene glycol. Cryoprotectant : 10% ethylene glycol.
PH range: 8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.97239 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Oct 15, 2009
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97239 Å / Relative weight: 1
ReflectionResolution: 1.05→50 Å / Num. obs: 60686 / % possible obs: 99.5 % / Redundancy: 5.05 % / Rmerge(I) obs: 0.074 / Net I/σ(I): 11.16
Reflection shellResolution: 1.05→1.11 Å / Redundancy: 4.65 % / Rmerge(I) obs: 0.481 / Mean I/σ(I) obs: 0.432 / % possible all: 98.6

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Processing

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

2oss


Resolution: 1.05→39.14 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.961 / SU B: 0.432 / SU ML: 0.022 / Cross valid method: THROUGHOUT / ESU R: 0.029 / ESU R Free: 0.031 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.19195 3035 5 %RANDOM
Rwork0.17082 ---
obs0.17186 57651 99.53 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 11.245 Å2
Baniso -1Baniso -2Baniso -3
1-0.57 Å2-0 Å20 Å2
2---0.3 Å20 Å2
3----0.27 Å2
Refinement stepCycle: LAST / Resolution: 1.05→39.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1062 0 33 164 1259
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.030.021186
X-RAY DIFFRACTIONr_bond_other_d0.0030.021124
X-RAY DIFFRACTIONr_angle_refined_deg2.4172.0051622
X-RAY DIFFRACTIONr_angle_other_deg1.2993.0052600
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2495138
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.46425.51758
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.12915211
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.798155
X-RAY DIFFRACTIONr_chiral_restr0.1530.2166
X-RAY DIFFRACTIONr_gen_planes_refined0.0140.0211350
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02272
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_it1.360.873534
X-RAY DIFFRACTIONr_mcbond_other1.3520.867533
X-RAY DIFFRACTIONr_mcangle_it1.8131.309675
X-RAY DIFFRACTIONr_mcangle_other1.8161.315676
X-RAY DIFFRACTIONr_scbond_it2.4181.108652
X-RAY DIFFRACTIONr_scbond_other2.4161.109653
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.4671.583947
X-RAY DIFFRACTIONr_long_range_B_refined5.5068.5491598
X-RAY DIFFRACTIONr_long_range_B_other5.5048.5521599
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.051→1.078 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.273 216 -
Rwork0.262 4108 -
obs--97.81 %

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