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- PDB-6ft3: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 6ft3
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with a 3,5-dimethylisoxazol ligand
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION / Bromodomain / ligand / isoxazole / Structural Genomics / Structural Genomics Consortium / SGC
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-E5T / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.28 Å
AuthorsFilippakopoulos, P. / Picaud, S. / Pike, A.C.W. / Krojer, T. / Conway, S.J. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Structural Genomics Consortium (SGC)
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust095751/Z/11/Z United Kingdom
CitationJournal: Bioorg.Med.Chem. / Year: 2018
Title: BET bromodomain ligands: Probing the WPF shelf to improve BRD4 bromodomain affinity and metabolic stability.
Authors: Jennings, L.E. / Schiedel, M. / Hewings, D.S. / Picaud, S. / Laurin, C.M.C. / Bruno, P.A. / Bluck, J.P. / Scorah, A.R. / See, L. / Reynolds, J.K. / Moroglu, M. / Mistry, I.N. / Hicks, A. / ...Authors: Jennings, L.E. / Schiedel, M. / Hewings, D.S. / Picaud, S. / Laurin, C.M.C. / Bruno, P.A. / Bluck, J.P. / Scorah, A.R. / See, L. / Reynolds, J.K. / Moroglu, M. / Mistry, I.N. / Hicks, A. / Guzanov, P. / Clayton, J. / Evans, C.N.G. / Stazi, G. / Biggin, P.C. / Mapp, A.K. / Hammond, E.M. / Humphreys, P.G. / Filippakopoulos, P. / Conway, S.J.
History
DepositionFeb 20, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 18, 2018Provider: repository / Type: Initial release
Revision 1.1Apr 24, 2019Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / citation ...chem_comp / citation / citation_author / entity / pdbx_database_proc / pdbx_entity_nonpoly
Item: _chem_comp.name / _citation.country ..._chem_comp.name / _citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Revision 1.2Jan 17, 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)15,4213
Polymers15,0991
Non-polymers3212
Water3,315184
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area200 Å2
ΔGint3 kcal/mol
Surface area7550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)37.549, 44.453, 78.715
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): R3 / 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-E5T / 3-[(~{R})-cyclopropyl(oxidanyl)methyl]-5-(3,5-dimethyl-1,2-oxazol-4-yl)phenol


Mass: 259.300 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H17NO3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 184 / 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: 2.18 Å3/Da / Density % sol: 43.46 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 0.1 M K(citrate) 0.1 M cacodylate pH 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.96861 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Dec 18, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96861 Å / Relative weight: 1
ReflectionResolution: 1.279→29.47 Å / Num. obs: 34700 / % possible obs: 99.6 % / Redundancy: 5.9 % / Rmerge(I) obs: 0.083 / Rpim(I) all: 0.036 / Rrim(I) all: 0.091 / Rsym value: 0.083 / Net I/av σ(I): 4.9 / Net I/σ(I): 10.8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) allRsym value% possible all
1.28-1.354.40.5221.448720.2730.5920.52297.3
1.35-1.435.50.367247390.1710.4060.367100
1.43-1.535.90.2532.844730.1130.2780.25399.9
1.53-1.656.50.1833.841650.0780.1990.183100
1.65-1.816.50.1394.938440.0590.1520.13999.9
1.81-2.026.30.1026.335110.0440.1120.102100
2.02-2.346.50.0787.831150.0330.0850.078100
2.34-2.866.50.0688.826420.0290.0740.068100
2.86-4.046.30.0569.321000.0240.0610.056100
4.04-29.475.70.056912390.0250.0620.05699.7

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å28.69 Å
Translation2.5 Å28.69 Å

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Processing

Software
NameVersionClassification
SCALA3.3.22data scaling
PHASER2.5.7phasing
REFMACrefinement
PDB_EXTRACT3.24data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Ensemble of 2OSS, 2OUO, 2GRC, 2OO1, 3DAI, 3D7C, 3DWY

2oss

2ouo

2grc

2oo1

3dai

3d7c

3dwy


Resolution: 1.28→29.47 Å / Cor.coef. Fo:Fc: 0.976 / Cor.coef. Fo:Fc free: 0.96 / SU B: 1.775 / SU ML: 0.034 / SU R Cruickshank DPI: 0.0471 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.047 / ESU R Free: 0.048
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1845 1652 4.8 %RANDOM
Rwork0.1471 ---
obs0.1488 32945 99.55 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 60.16 Å2 / Biso mean: 15.086 Å2 / Biso min: 6.99 Å2
Baniso -1Baniso -2Baniso -3
1-0.5 Å20 Å20 Å2
2---0.22 Å20 Å2
3----0.28 Å2
Refinement stepCycle: final / Resolution: 1.28→29.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1062 0 23 184 1269
Biso mean--21.19 27 -
Num. residues----127
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.021139
X-RAY DIFFRACTIONr_bond_other_d0.0030.021046
X-RAY DIFFRACTIONr_angle_refined_deg2.8471.9851555
X-RAY DIFFRACTIONr_angle_other_deg1.152.9832455
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6035132
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.57225.63655
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.91315203
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.471154
X-RAY DIFFRACTIONr_chiral_restr0.1090.2163
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0211230
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02210
X-RAY DIFFRACTIONr_rigid_bond_restr2.41332185
X-RAY DIFFRACTIONr_sphericity_free20.9595117
X-RAY DIFFRACTIONr_sphericity_bonded7.94952218
LS refinement shellResolution: 1.28→1.313 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.351 125 -
Rwork0.337 2288 -
all-2413 -
obs--94.96 %

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