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- PDB-6fo5: FIRST DOMAIN OF HUMAN BROMODOMAIN BRD4 IN COMPLEX WITH INHIBITOR #17 -

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Basic information

Entry
Database: PDB / ID: 6fo5
TitleFIRST DOMAIN OF HUMAN BROMODOMAIN BRD4 IN COMPLEX WITH INHIBITOR #17
ComponentsBromodomain-containing protein 4
KeywordsDNA BINDING PROTEIN / 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 / 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-DZH / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 0.95 Å
AuthorsRaux, B. / Betzi, S.
Funding support France, 4items
OrganizationGrant numberCountry
Canceropole PACA Institut National du Cancer Conseil Regional PACA France
Fondation FRM pour la Recherche Medicale France
Agence Nationale de la Recherche (ANR)ANR-15-CE18-0023 France
Integrated Structural Biology (FRISBI)ANR-10-INSB-05-01 France
CitationJournal: J. Med. Chem. / Year: 2018
Title: Integrated Strategy for Lead Optimization Based on Fragment Growing: The Diversity-Oriented-Target-Focused-Synthesis Approach.
Authors: Hoffer, L. / Voitovich, Y.V. / Raux, B. / Carrasco, K. / Muller, C. / Fedorov, A.Y. / Derviaux, C. / Amouric, A. / Betzi, S. / Horvath, D. / Varnek, A. / Collette, Y. / Combes, S. / Roche, P. / Morelli, X.
History
DepositionFeb 6, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 20, 2018Provider: repository / Type: Initial release
Revision 1.1Jul 4, 2018Group: Data collection / Database references / Category: citation / Item: _citation.title
Revision 1.2Jul 25, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jan 17, 2024Group: Author supporting evidence / Data collection ...Author supporting evidence / Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_audit_support / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_audit_support.funding_organization

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,6843
Polymers15,0991
Non-polymers5852
Water3,117173
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area140 Å2
ΔGint1 kcal/mol
Surface area7680 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.284, 47.498, 58.468
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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: pDEST17 / Production host: Escherichia coli BL21 (bacteria) / Variant (production host): star / References: UniProt: O60885
#2: Chemical ChemComp-DZH / ~{N}-[[4-[[7-ethyl-2,6-bis(oxidanylidene)purin-3-yl]methyl]phenyl]methyl]-2-oxidanylidene-1,3,4,5-tetrahydro-1-benzazepine-7-sulfonamide


Mass: 522.576 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H26N6O5S
#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.: 173 / 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: 2.04 Å3/Da / Density % sol: 39.7 %
Crystal growTemperature: 292 K / Method: evaporation / pH: 8.5
Details: 2.5mM of #17 inhibitor (in DMSO) final concentration. Ratio 1:1 (protein:precipitant. 12mg/mL of BRD4(BD1) protein. Precipitant agent: 0.3M NaNO3; 0.1M NaCl; 22% (w/v) PEG3350; 10% (w/v) ...Details: 2.5mM of #17 inhibitor (in DMSO) final concentration. Ratio 1:1 (protein:precipitant. 12mg/mL of BRD4(BD1) protein. Precipitant agent: 0.3M NaNO3; 0.1M NaCl; 22% (w/v) PEG3350; 10% (w/v) ethylene glycol. Cryoprotectant: 10 % (w/v) glycerol.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.9 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 29, 2016
RadiationMonochromator: NULL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionResolution: 0.95→36.87 Å / Num. obs: 78067 / % possible obs: 99.61 % / Redundancy: 6.8 % / Biso Wilson estimate: 9.83 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.04761 / Rpim(I) all: 0.01942 / Rrim(I) all: 0.05153 / Net I/σ(I): 16.41
Reflection shellResolution: 0.95→0.98 Å / Redundancy: 4.7 % / Rmerge(I) obs: 1.617 / Mean I/σ(I) obs: 0.78 / Num. unique obs: 7498 / CC1/2: 0.434 / Rpim(I) all: 0.8059 / Rrim(I) all: 1.819 / % possible all: 96.26

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Processing

Software
NameVersionClassification
REFMAC5.8.0189refinement
XDS0.53data reduction
XDS0.53data scaling
Coot0.8.6model building
PHASER2.7.17phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OSS

2oss


Resolution: 0.95→36.87 Å / Cor.coef. Fo:Fc: 0.983 / Cor.coef. Fo:Fc free: 0.98 / SU B: 0.703 / SU ML: 0.016 / Cross valid method: THROUGHOUT / ESU R: 0.019 / ESU R Free: 0.02 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.15362 3929 5 %RANDOM
Rwork0.1355 ---
obs0.13641 74651 99.28 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 15.31 Å2
Baniso -1Baniso -2Baniso -3
1-0.24 Å2-0 Å2-0 Å2
2---1.34 Å20 Å2
3---1.1 Å2
Refinement stepCycle: 1 / Resolution: 0.95→36.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1062 0 41 173 1276
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.030.0191185
X-RAY DIFFRACTIONr_bond_other_d0.0060.021080
X-RAY DIFFRACTIONr_angle_refined_deg2.3631.9661622
X-RAY DIFFRACTIONr_angle_other_deg1.6972.9692537
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5135136
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.26125.71456
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.60115208
X-RAY DIFFRACTIONr_dihedral_angle_4_deg24.807154
X-RAY DIFFRACTIONr_chiral_restr0.180.2166
X-RAY DIFFRACTIONr_gen_planes_refined0.0140.0211290
X-RAY DIFFRACTIONr_gen_planes_other0.0060.02219
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_it10.2741.255529
X-RAY DIFFRACTIONr_mcbond_other10.2811.252528
X-RAY DIFFRACTIONr_mcangle_it8.8211.867664
X-RAY DIFFRACTIONr_mcangle_other8.8151.869665
X-RAY DIFFRACTIONr_scbond_it4.91.515656
X-RAY DIFFRACTIONr_scbond_other4.8981.515656
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.8452.139957
X-RAY DIFFRACTIONr_long_range_B_refined7.16915.8261463
X-RAY DIFFRACTIONr_long_range_B_other7.16715.8341464
X-RAY DIFFRACTIONr_rigid_bond_restr8.80332265
X-RAY DIFFRACTIONr_sphericity_free26.4765107
X-RAY DIFFRACTIONr_sphericity_bonded15.93952293
LS refinement shellResolution: 0.947→0.971 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.522 263 -
Rwork0.528 4996 -
obs--90.86 %

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