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

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Basic information

Entry
Database: PDB / ID: 5dlx
TitleFIRST DOMAIN OF HUMAN BROMODOMAIN BRD4 IN COMPLEX WITH INHIBITOR N-{3-[4-(3-chlorophenyl)piperazin-1-yl]propyl}-1-{3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl}piperidine-4-carboxamide
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION / INHIBITOR / HISTONE / EPIGENETIC READER / BROMODOMAIN / BRD4 / 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 / 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 / condensed nuclear chromosome / histone reader activity / : ...RNA polymerase II C-terminal domain binding / P-TEFb complex binding / negative regulation of DNA damage checkpoint / 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 / condensed nuclear chromosome / histone reader activity / : / positive regulation of transcription elongation by RNA polymerase II / transcription coregulator activity / p53 binding / chromosome / regulation of inflammatory response / histone binding / Potential therapeutics for SARS / positive regulation of canonical NF-kappaB signal transduction / transcription coactivator activity / 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 / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-5D2 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsRaux, B. / Rebuffet, E. / Betzi, S. / Morelli, X.
CitationJournal: Acs Chem.Biol. / Year: 2016
Title: Protein-Protein Interaction Inhibition (2P2I)-Oriented Chemical Library Accelerates Hit Discovery.
Authors: Milhas, S. / Raux, B. / Betzi, S. / Derviaux, C. / Roche, P. / Restouin, A. / Basse, M.J. / Rebuffet, E. / Lugari, A. / Badol, M. / Kashyap, R. / Lissitzky, J.C. / Eydoux, C. / Hamon, V. / ...Authors: Milhas, S. / Raux, B. / Betzi, S. / Derviaux, C. / Roche, P. / Restouin, A. / Basse, M.J. / Rebuffet, E. / Lugari, A. / Badol, M. / Kashyap, R. / Lissitzky, J.C. / Eydoux, C. / Hamon, V. / Gourdel, M.E. / Combes, S. / Zimmermann, P. / Aurrand-Lions, M. / Roux, T. / Rogers, C. / Muller, S. / Knapp, S. / Trinquet, E. / Collette, Y. / Guillemot, J.C. / Morelli, X.
History
DepositionSep 7, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jun 1, 2016Provider: repository / Type: Initial release
Revision 1.1Aug 31, 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)15,5962
Polymers15,0991
Non-polymers4971
Water66737
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area7540 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.723, 48.509, 58.094
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 42-168
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: PLASMID / Details (production host): pDEST17 / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / Variant (production host): star / References: UniProt: O60885
#2: Chemical ChemComp-5D2 / N-{3-[4-(3-chlorophenyl)piperazin-1-yl]propyl}-1-(3-methyl[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidine-4-carboxamide


Mass: 497.036 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H33ClN8O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 37 / 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: 1.96 Å3/Da / Density % sol: 37.31 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: Ratio 1:1 (protein:precipitant). 12 mg/mL Brd4_BD1 protein. Protein buffer 10 mM HEPES (pH 7.5) 150 mM NaCl. Precipitant agent 22 % (w/v) PEG 3350, 10% (w/v) ethylene glycol 30 % (w/v), 0.3 ...Details: Ratio 1:1 (protein:precipitant). 12 mg/mL Brd4_BD1 protein. Protein buffer 10 mM HEPES (pH 7.5) 150 mM NaCl. Precipitant agent 22 % (w/v) PEG 3350, 10% (w/v) ethylene glycol 30 % (w/v), 0.3 M NaFormate. 1.0 mM inhibitor (in DMSO) final concentration. Cryoprotection with 10 % (w/v) glycerol
PH range: 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.9677 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Apr 15, 2015
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9677 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 9664 / % possible obs: 99.3 % / Redundancy: 4.83 % / Rsym value: 0.042 / Net I/σ(I): 20.09
Reflection shellResolution: 1.9→2.02 Å / Redundancy: 4.59 % / Mean I/σ(I) obs: 3.73 / Rsym value: 0.379 / % possible all: 97.8

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Processing

Software
NameVersionClassification
XDSjun 17, 2015data reduction
XDSjun 17, 2015data scaling
PHASERversion 2.5.6phasing
REFMAC5.8.0131refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OSS

2oss


Resolution: 1.9→37.23 Å / Cor.coef. Fo:Fc: 0.984 / Cor.coef. Fo:Fc free: 0.963 / SU B: 9.763 / SU ML: 0.118 / Cross valid method: THROUGHOUT / ESU R Free: 0.14 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20707 484 5 %RANDOM
Rwork0.12547 ---
obs0.12959 9180 99.31 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 42.711 Å2
Baniso -1Baniso -2Baniso -3
1--0.31 Å20 Å20 Å2
2--2.31 Å2-0 Å2
3----1.99 Å2
Refinement stepCycle: LAST / Resolution: 1.9→37.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1043 0 35 37 1115
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0280.021112
X-RAY DIFFRACTIONr_bond_other_d0.0050.021063
X-RAY DIFFRACTIONr_angle_refined_deg2.3162.0041514
X-RAY DIFFRACTIONr_angle_other_deg1.2513.0122461
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4985124
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.35625.76952
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.09115193
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.734153
X-RAY DIFFRACTIONr_chiral_restr0.1210.2157
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0211228
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02248
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_it8.3143.688499
X-RAY DIFFRACTIONr_mcbond_other7.8913.68498
X-RAY DIFFRACTIONr_mcangle_it9.1975.55622
X-RAY DIFFRACTIONr_mcangle_other9.3675.558623
X-RAY DIFFRACTIONr_scbond_it10.8854.48613
X-RAY DIFFRACTIONr_scbond_other10.8774.478614
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other12.2716.408893
X-RAY DIFFRACTIONr_long_range_B_refined11.39431.1141306
X-RAY DIFFRACTIONr_long_range_B_other11.42131.0821296
X-RAY DIFFRACTIONr_rigid_bond_restr5.03532175
X-RAY DIFFRACTIONr_sphericity_free33.033513
X-RAY DIFFRACTIONr_sphericity_bonded27.12852165
LS refinement shellResolution: 1.901→1.951 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.435 34 -
Rwork0.191 644 -
obs--95.76 %

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