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- PDB-5d25: First bromodomain of BRD4 bound to inhibitor XD27 -

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Basic information

Entry
Database: PDB / ID: 5d25
TitleFirst bromodomain of BRD4 bound to inhibitor XD27
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION / Gene regulation / Inhibitor / bromodomain
Function / homology
Function and homology information


RNA polymerase II C-terminal domain binding / P-TEFb complex binding / negative regulation of DNA damage checkpoint / histone H4 reader activity / host-mediated suppression of viral transcription / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of T-helper 17 cell lineage commitment / : / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome ...RNA polymerase II C-terminal domain binding / P-TEFb complex binding / negative regulation of DNA damage checkpoint / histone H4 reader activity / host-mediated suppression of viral transcription / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of T-helper 17 cell lineage commitment / : / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / transcription coregulator activity / positive regulation of transcription elongation by RNA polymerase II / p53 binding / chromosome / regulation of inflammatory response / histone binding / Potential therapeutics for SARS / transcription coactivator activity / positive regulation of canonical NF-kappaB signal transduction / 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 / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-56M / (R,R)-2,3-BUTANEDIOL / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsWohlwend, D. / Huegle, M. / Gerhardt, S.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research FoundationWO2012/1-1 Germany
CitationJournal: J.Med.Chem. / Year: 2016
Title: 4-Acyl Pyrrole Derivatives Yield Novel Vectors for Designing Inhibitors of the Acetyl-Lysine Recognition Site of BRD4(1).
Authors: Hugle, M. / Lucas, X. / Weitzel, G. / Ostrovskyi, D. / Breit, B. / Gerhardt, S. / Einsle, O. / Gunther, S. / Wohlwend, D.
History
DepositionAug 5, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jan 20, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 9, 2016Group: Database references
Revision 1.2Sep 6, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3May 8, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,6024
Polymers15,0121
Non-polymers5903
Water1,856103
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area520 Å2
ΔGint0 kcal/mol
Surface area7450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.360, 49.810, 58.050
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: 15012.301 Da / Num. of mol.: 1 / Fragment: UNP residues 43-168 / Mutation: T43M
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) / References: UniProt: O60885
#2: Chemical ChemComp-56M / 4-acetyl-N-[5-(diethylsulfamoyl)-2-hydroxyphenyl]-3,5-dimethyl-1H-pyrrole-2-carboxamide


Mass: 407.484 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H25N3O5S
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-BU3 / (R,R)-2,3-BUTANEDIOL


Mass: 90.121 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 103 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 1.9 Å3/Da / Density % sol: 35.1 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: PEG3350, Hepes

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Sep 3, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.6→39.4 Å / Num. obs: 12993 / % possible obs: 99.3 % / Redundancy: 6.4 % / Rmerge(I) obs: 0.108 / Net I/σ(I): 10.4
Reflection shellResolution: 1.6→1.69 Å / Rmerge(I) obs: 0.615 / Mean I/σ(I) obs: 3.2 / Num. unique all: 1872 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0071refinement
SCALA3.3.21data scaling
PHASER2.5.6phasing
iMOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→37.8 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.953 / SU B: 4.492 / SU ML: 0.074 / Cross valid method: THROUGHOUT / ESU R: 0.13 / ESU R Free: 0.111 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.19573 1272 9.8 %RANDOM
Rwork0.17481 ---
obs0.17682 11677 99.04 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 17.734 Å2
Baniso -1Baniso -2Baniso -3
1--1.09 Å2-0 Å20 Å2
2--2.19 Å20 Å2
3----1.1 Å2
Refinement stepCycle: 1 / Resolution: 1.7→37.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1037 0 40 103 1180
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.021141
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.2292.0061559
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.2835131
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.14425.84953
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.23615200
X-RAY DIFFRACTIONr_dihedral_angle_4_deg7.976153
X-RAY DIFFRACTIONr_chiral_restr0.0710.2164
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022880
X-RAY DIFFRACTIONr_gen_planes_other
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_it0.2570.887515
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.4161.328649
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.4691.014626
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined3.3159.1314921
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.7→1.744 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.344 85 -
Rwork0.274 846 -
obs--99.89 %
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)
16.7148-2.1884-6.627.78650.60719.82290.25280.0840.0737-0.01230.00260.1717-0.0014-0.3309-0.25550.0719-0.0056-0.04690.07720.00630.0536-0.660961.02557.9354
24.4413-0.1070.85950.8248-0.2246.1039-0.04420.29610.0267-0.1314-0.0058-0.00120.13850.16460.050.0718-0.0163-0.00260.0268-0.00010.053318.45852.7420.198
32.4661-1.2482-0.01833.0432-0.37811.98340.0025-0.1903-0.06840.09740.00130.0540.0156-0.1397-0.00380.0158-0.0206-0.00470.04860.01130.00466.469958.363217.4768
44.1191-0.4543-2.76040.8920.95634.65450.00510.149-0.0888-0.03090.07550.04420.0021-0.0803-0.08060.0134-0.0111-0.01530.02110.01160.027114.961656.27133.3676
50.4611-0.44040.10142.12830.60351.8566-0.0155-0.15840.02060.28990.0353-0.10640.0022-0.0359-0.01980.0541-0.0183-0.01330.0655-0.00010.036512.896663.926421.1317
610.9286-2.4774-8.60914.3852.01528.71520.04630.17940.0165-0.1105-0.0423-0.4775-0.09240.3655-0.0040.0539-0.0363-0.02760.16340.00340.113626.667356.165614.0054
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A43 - 49
2X-RAY DIFFRACTION2A50 - 70
3X-RAY DIFFRACTION3A71 - 106
4X-RAY DIFFRACTION4A107 - 127
5X-RAY DIFFRACTION5A128 - 153
6X-RAY DIFFRACTION6A154 - 166

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