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- PDB-4hby: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 4hby
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with a quinazolin ligand
ComponentsBromodomain-containing protein 4
KeywordsSIGNALING PROTEIN/INHIBITOR / BROMODOMAIN / CAP / HUNK1 / MCAP / MITOTIC CHROMOSOME ASSOCIATED PROTEIN / CELL CYCLE / STRUCTURAL GENOMICS CONSORTIUM / SGC / SIGNALING PROTEIN-INHIBITOR complex
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 / histone reader activity / RNA polymerase II CTD heptapeptide repeat kinase 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 / histone reader activity / RNA polymerase II CTD heptapeptide repeat kinase 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 II / Brdt, bromodomain, repeat I / 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 II / Brdt, bromodomain, repeat I / 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-13F / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.59 Å
AuthorsFilippakopoulos, P. / Picaud, S. / Qi, J. / Felletar, I. / von Delft, F. / Bountra, C. / Arrowsmith, C.H. / Edwards, A. / Fish, P.V. / Bunnage, M.E. ...Filippakopoulos, P. / Picaud, S. / Qi, J. / Felletar, I. / von Delft, F. / Bountra, C. / Arrowsmith, C.H. / Edwards, A. / Fish, P.V. / Bunnage, M.E. / Cook, A.S. / Owen, D.R. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: J.Med.Chem. / Year: 2012
Title: Identification of a Chemical Probe for Bromo and Extra C-Terminal Bromodomain Inhibition through Optimization of a Fragment-Derived Hit.
Authors: Fish, P.V. / Filippakopoulos, P. / Bish, G. / Brennan, P.E. / Bunnage, M.E. / Cook, A.S. / Federov, O. / Gerstenberger, B.S. / Jones, H. / Knapp, S. / Marsden, B. / Nocka, K. / Owen, D.R. / ...Authors: Fish, P.V. / Filippakopoulos, P. / Bish, G. / Brennan, P.E. / Bunnage, M.E. / Cook, A.S. / Federov, O. / Gerstenberger, B.S. / Jones, H. / Knapp, S. / Marsden, B. / Nocka, K. / Owen, D.R. / Philpott, M. / Picaud, S. / Primiano, M.J. / Ralph, M.J. / Sciammetta, N. / Trzupek, J.D.
History
DepositionSep 28, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 31, 2012Provider: repository / Type: Initial release
Revision 1.1Nov 14, 2012Group: Database references
Revision 1.2Dec 12, 2012Group: Database references
Revision 1.3Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)15,4793
Polymers15,0991
Non-polymers3792
Water2,360131
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)43.700, 48.470, 61.340
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 (E. coli) / Strain (production host): BL21(DE3)-R3 / References: UniProt: O60885
#2: Chemical ChemComp-13F / 3-methyl-2-oxo-N-phenyl-1,2,3,4-tetrahydroquinazoline-6-sulfonamide


Mass: 317.363 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H15N3O3S
#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.: 131 / 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: 2.15 Å3/Da / Density % sol: 42.82 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.2M KSCN, 20% PEG3350, 10% EtGly, pH 7.5, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Feb 11, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionRedundancy: 4.6 % / Av σ(I) over netI: 4 / Number: 84465 / Rsym value: 0.099 / D res high: 1.585 Å / D res low: 35.591 Å / Num. obs: 18169 / % possible obs: 99.3
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsRsym valueRedundancy
5.0135.5999.610.070.074.3
3.545.0199.210.070.074.3
2.893.5499.810.0890.0894.5
2.512.8910010.090.094.6
2.242.5199.910.0980.0984.7
2.052.2499.710.1170.1174.7
1.892.0599.510.1730.1734.7
1.771.8999.310.2610.2614.8
1.671.779910.4350.4354.8
1.591.6798.310.6540.6544.6
ReflectionResolution: 1.585→38.03 Å / Num. all: 18297 / Num. obs: 18169 / % possible obs: 99.3 % / Redundancy: 4.6 % / Biso Wilson estimate: 20 Å2 / Rmerge(I) obs: 0.099 / Rsym value: 0.099 / Net I/σ(I): 8.5
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
1.59-1.674.60.6541.21178425860.65498.3
1.67-1.774.80.4351.71172024360.43599
1.77-1.894.80.2612.81105423230.26199.3
1.89-2.054.70.1734.11035721810.17399.5
2.05-2.244.70.1175.6946220090.11799.7
2.24-2.514.70.0986.4865418410.09899.9
2.51-2.894.60.096.5757016360.09100
2.89-3.544.50.0896.3628313960.08999.8
3.54-5.014.30.078477211010.0799.2
5.01-35.5914.30.077.328096600.0799.6

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å35.59 Å
Translation2.5 Å35.59 Å

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Processing

Software
NameVersionClassificationNB
SCALA3.3.20data scaling
PHASER2.3.0phasing
REFMACrefinement
PDB_EXTRACT3.11data extraction
CrystalCleardata collection
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OSS

2oss


Resolution: 1.59→38.03 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.943 / WRfactor Rfree: 0.2463 / WRfactor Rwork: 0.1937 / Occupancy max: 1 / Occupancy min: 0.3 / FOM work R set: 0.8466 / SU B: 3.857 / SU ML: 0.072 / SU R Cruickshank DPI: 0.0962 / SU Rfree: 0.1045 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.096 / ESU R Free: 0.104 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES: WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2388 924 5.1 %RANDOM
Rwork0.185 ---
all0.1876 18283 --
obs0.1876 18128 99.15 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 120.76 Å2 / Biso mean: 26.6523 Å2 / Biso min: 8.45 Å2
Baniso -1Baniso -2Baniso -3
1-0.42 Å20 Å20 Å2
2--0.6 Å20 Å2
3----1.02 Å2
Refinement stepCycle: LAST / Resolution: 1.59→38.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1053 0 26 131 1210
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.021163
X-RAY DIFFRACTIONr_bond_other_d0.0010.02785
X-RAY DIFFRACTIONr_angle_refined_deg1.6412.0361591
X-RAY DIFFRACTIONr_angle_other_deg0.98631920
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9315128
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.91625.84953
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.87515192
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.349153
X-RAY DIFFRACTIONr_chiral_restr0.0980.2160
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0211497
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02230
LS refinement shellResolution: 1.585→1.626 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.358 63 -
Rwork0.341 1130 -
all-1193 -
obs--96.76 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.0640.8523-0.56841.0559-1.06581.3055-0.22810.0681-0.0617-0.2-0.0085-0.17290.16170.06610.23660.08550.01380.02510.04950.01550.061719.58222.58212.8848
20.29520.0475-0.18510.9563-1.08681.4669-0.0759-0.0452-0.00680.0740.0243-0.0006-0.02790.01530.05160.05480.0062-0.00910.04760.00880.046813.86886.380511.6023
32.6998-1.55610.03351.7152-1.01381.2309-0.4822-0.0615-0.07660.5036-0.1719-0.4723-0.23950.32010.6540.1820.0056-0.11240.15340.15920.330325.53934.198117.206
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A42 - 76
2X-RAY DIFFRACTION2A77 - 141
3X-RAY DIFFRACTION3A142 - 168

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