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

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Basic information

Entry
Database: PDB / ID: 5egu
TitleFIRST DOMAIN OF HUMAN BROMODOMAIN BRD4 IN COMPLEX WITH INHIBITOR 3-Butyl-8-(6-butyl-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylsulfanylmethyl)-7-ethyl-3,7-dihydropurine-2,6-dione
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION / INHIBITOR / HISTONE / EPIGENETIC READER / BROMODOMAIN / BRD4 / Brd4_BD1 / Brd4_BD1 06-NOV
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-5NQ / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.21 Å
AuthorsRaux, B. / Rebuffet, E. / Betzi, S. / Priet, 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 27, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jan 20, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 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

Downloads & links

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
B: Bromodomain-containing protein 4
C: Bromodomain-containing protein 4
D: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,3989
Polymers60,3984
Non-polymers2,0015
Water4,504250
1
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,6463
Polymers15,0991
Non-polymers5472
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,5842
Polymers15,0991
Non-polymers4851
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,5842
Polymers15,0991
Non-polymers4851
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,5842
Polymers15,0991
Non-polymers4851
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)69.686, 83.612, 107.391
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.: 4 / Fragment: N-TERMINAL BROMODOMAIN, RESIDUES 42-168
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-5NQ / 3-butyl-8-[(6-butyl-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)sulfanylmethyl]-7-ethyl-purine-2,6-dione


Mass: 484.618 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H32N8O2S
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 250 / 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: 2.59 Å3/Da / Density % sol: 52.83 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: Ratio 1:1 (protein:precipitant). 25 mg/mL BRD4_BD1 protein. 1.0 mM inhibitor (in DMSO) final concentration. Protein buffer: 0.01M HEPES (pH 7.5), 0.15M NaCl. Precipitant agent : 0.2M ...Details: Ratio 1:1 (protein:precipitant). 25 mg/mL BRD4_BD1 protein. 1.0 mM inhibitor (in DMSO) final concentration. Protein buffer: 0.01M HEPES (pH 7.5), 0.15M NaCl. Precipitant agent : 0.2M Ammonium sulfate, 0.1M Tris pH 8.5, 25% PEG3350. Cryoprotectant : 10% ethylene glycol.
PH range: 8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: BRUKER AXS MICROSTAR / Wavelength: 1.54179 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Nov 14, 2006
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54179 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. obs: 59187 / % possible obs: 97.8 % / Redundancy: 4.63 % / Rmerge(I) obs: 0.104 / Net I/σ(I): 13.15
Reflection shellResolution: 2.21→2.35 Å / Redundancy: 4.52 % / Rmerge(I) obs: 0.48 / Mean I/σ(I) obs: 3.44 / % possible all: 95.2

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Processing

Software
NameVersionClassification
XDS17 jun 2015data reduction
XDS17 jun 2015data scaling
PHASER2.5.6phasing
REFMAC5.8.0131refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OSS

2oss


Resolution: 2.21→45.18 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.902 / SU B: 5.087 / SU ML: 0.13 / Cross valid method: THROUGHOUT / ESU R: 0.247 / ESU R Free: 0.203 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2353 1566 5 %RANDOM
Rwork0.18474 ---
obs0.18724 29752 97.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 25.187 Å2
Baniso -1Baniso -2Baniso -3
1-0.39 Å20 Å20 Å2
2--0.67 Å2-0 Å2
3----1.06 Å2
Refinement stepCycle: LAST / Resolution: 2.21→45.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3934 0 140 250 4324
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.024193
X-RAY DIFFRACTIONr_bond_other_d0.0060.024001
X-RAY DIFFRACTIONr_angle_refined_deg1.8322.0035708
X-RAY DIFFRACTIONr_angle_other_deg1.2893.0069216
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4425464
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.46225.821201
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.21415729
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.5131510
X-RAY DIFFRACTIONr_chiral_restr0.0990.2591
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0214640
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02950
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_it2.1542.2921871
X-RAY DIFFRACTIONr_mcbond_other2.1512.291870
X-RAY DIFFRACTIONr_mcangle_it3.2463.4072330
X-RAY DIFFRACTIONr_mcangle_other3.2463.412331
X-RAY DIFFRACTIONr_scbond_it2.72.5612322
X-RAY DIFFRACTIONr_scbond_other2.6992.5612322
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.273.7163379
X-RAY DIFFRACTIONr_long_range_B_refined5.64418.6465421
X-RAY DIFFRACTIONr_long_range_B_other5.64418.6485421
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.213→2.27 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.267 109 -
Rwork0.206 2077 -
obs--94.22 %

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