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- PDB-6mh7: Crystal structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 6mh7
TitleCrystal structure of the first bromodomain of human BRD4 in complex with SKT-68, a 1,4,5-trisubstituted imidazole analogue
ComponentsBromodomain-containing protein 4
KeywordsPROTEIN BINDING/INHIBITOR / bromodomain / CAP / HUNK1 / MCAP / PROTEIN BINDING-INHIBITOR complex / inhibitor / transcription-inhibitor complex / inflammation / 19F-NMR / MAP-kinase inhibition
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 / chromatin / 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 / NET domain superfamily / NET domain profile. / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain-like / Histone Acetyltransferase; Chain A ...Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / NET domain superfamily / NET domain profile. / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / 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-JQY / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.74 Å
AuthorsZhu, J.-Y. / Schonbrunn, E.
Funding support United States, 2items
OrganizationGrant numberCountry
National Science Foundation (NSF, United States)CHE-1352019 United States
American Heart Association15SDG25710427 United States
CitationJournal: J.Med.Chem. / Year: 2018
Title: Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase-Bromodomain Inhibitor.
Authors: Divakaran, A. / Talluri, S.K. / Ayoub, A.M. / Mishra, N.K. / Cui, H. / Widen, J.C. / Berndt, N. / Zhu, J.Y. / Carlson, A.S. / Topczewski, J.J. / Schonbrunn, E.K. / Harki, D.A. / Pomerantz, W.C.K.
History
DepositionSep 17, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 7, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 27, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Oct 11, 2023Group: 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,4109
Polymers30,1992
Non-polymers1,2117
Water3,927218
1
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,7445
Polymers15,0991
Non-polymers6454
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,6664
Polymers15,0991
Non-polymers5673
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)41.750, 59.370, 111.820
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.: 2 / Fragment: UNP residues 44-168
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) / Strain (production host): BL21(DE3)-R3 / References: UniProt: O60885
#2: Chemical ChemComp-JQY / N-(3,4-dimethylphenyl)-4-[4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine


Mass: 442.531 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H27FN6 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


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


Mass: 18.015 Da / Num. of mol.: 218 / 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: 2.29 Å3/Da / Density % sol: 46.39 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 12.5 mg/mL BRD4, 5 mM HEPES, pH 7.5, 50 mM sodium chloride, 0.5 mM DTT, 50 mM Tris, pH 8.5, 0.1 M ammonium sulfate, 12.5% PEG3350, 10% DMSO, 1 mM SKT-68

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Feb 17, 2016
RadiationMonochromator: Rosenbaum-Rock double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.74→39.113 Å / Num. obs: 29128 / % possible obs: 99.4 % / Redundancy: 7.267 % / Biso Wilson estimate: 18.1 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.04 / Rrim(I) all: 0.043 / Χ2: 0.993 / Net I/σ(I): 33.44
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
1.74-1.797.3790.3265.9420860.9560.3599.1
1.79-1.837.3640.2827.120690.9660.30399
1.83-1.897.390.2169.2420030.9820.23299
1.89-1.957.3490.17211.619350.9880.18599.2
1.95-2.017.3610.13614.4819060.9920.14699.3
2.01-2.087.3670.10318.9418510.9950.11199.5
2.08-2.167.3340.07924.1617600.9970.08599.5
2.16-2.257.3350.0727.4216970.9980.07599.4
2.25-2.357.2840.0631.0416680.9980.06499.5
2.35-2.467.3160.05533.6815770.9990.05999.6
2.46-2.597.2810.04738.3615150.9990.05199.5
2.59-2.757.2880.0444.3314140.9990.04399.9
2.75-2.947.2410.03252.3713550.9990.03599.9
2.94-3.187.2010.02860.0812660.9990.0399.3
3.18-3.487.130.02468.76117110.02599.7
3.48-3.897.1430.0277.34105410.02299.7
3.89-4.497.0870.01880.7194710.01999.9
4.49-5.56.9710.01878.8781510.019100
5.5-7.786.7730.01876.3165310.01999.7
7.78-39.1136.0730.01875.0838610.0298.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
XSCALEdata scaling
PHASERphasing
PHENIX1.9_1692refinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4O7B

4o7b


Resolution: 1.74→39.113 Å / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 16.68
RfactorNum. reflection% reflectionSelection details
Rfree0.1848 1223 4.2 %Random selection
Rwork0.1533 ---
obs0.1546 29118 99.4 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 162.63 Å2 / Biso mean: 27.5331 Å2 / Biso min: 9.1 Å2
Refinement stepCycle: final / Resolution: 1.74→39.113 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2124 0 170 218 2512
Biso mean--29.8 29.75 -
Num. residues----254
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.012291
X-RAY DIFFRACTIONf_angle_d1.2713115
X-RAY DIFFRACTIONf_chiral_restr0.047321
X-RAY DIFFRACTIONf_plane_restr0.006399
X-RAY DIFFRACTIONf_dihedral_angle_d13.186882
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 9

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.74-1.80960.2121330.16513028316199
1.8096-1.8920.22881330.16963030316399
1.892-1.99170.1811340.15783054318899
1.9917-2.11650.20251340.152530593193100
2.1165-2.27990.19781350.14773073320899
2.2799-2.50930.20711350.153430913226100
2.5093-2.87230.16951360.158631053241100
2.8723-3.61840.17531390.156431613300100
3.6184-39.12260.16951440.144732943438100
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)
17.74216.3123-5.79927.9128-5.23614.50820.1235-0.6549-0.48420.2155-0.4425-0.323-0.13530.59330.34560.24020.0031-0.01180.24330.0330.204625.4669-29.916648.6406
22.14450.342-0.81112.9414-2.62113.5406-0.209-0.161-0.09120.03050.11190.13240.3834-0.068-0.00840.18080.04750.03580.1543-0.0150.14085.9955-37.101446.9115
37.56331.65033.62352.03430.6254.3732-0.02740.31420.0257-0.14510.0729-0.06490.02210.2206-0.02540.14020.02270.03090.108-0.02550.090520.6367-24.969535.1683
42.15181.1944-1.1243.0374-1.30012.2023-0.0546-0.056-0.04690.01950.06880.06640.0639-0.0673-0.01460.11880.0166-0.00560.1044-0.00650.075813.964-25.295245.9828
52.69533.3004-2.76375.0702-2.3984.54470.0220.19670.14840.08330.12470.49430.1068-0.4878-0.1140.12630.00620.00830.20350.01210.18182.725-24.715439.2021
64.35590.71540.22261.0915-0.90844.1531-0.0981-0.42140.09450.06210.06910.12420.1723-0.3002-0.01520.16890.0670.00780.0965-0.01580.146412.4686-4.360148.5472
71.79890.503-0.50772.4152-0.74042.3927-0.0059-0.00570.09750.03250.00370.0469-0.15120.0559-0.00550.11750.0170.00510.0974-0.00050.095417.13045.420743.5018
86.12852.6607-1.95645.4275-1.21245.1508-0.08310.05170.05040.01320.17390.650.1038-0.5762-0.09350.14370.0318-0.0210.20850.02930.22514.18344.72638.9143
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 42 through 51 )A42 - 51
2X-RAY DIFFRACTION2chain 'A' and (resid 52 through 75 )A52 - 75
3X-RAY DIFFRACTION3chain 'A' and (resid 76 through 96 )A76 - 96
4X-RAY DIFFRACTION4chain 'A' and (resid 97 through 144 )A97 - 144
5X-RAY DIFFRACTION5chain 'A' and (resid 145 through 168 )A145 - 168
6X-RAY DIFFRACTION6chain 'B' and (resid 42 through 75 )B42 - 75
7X-RAY DIFFRACTION7chain 'B' and (resid 76 through 144 )B76 - 144
8X-RAY DIFFRACTION8chain 'B' and (resid 145 through 168 )B145 - 168

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