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- PDB-5d24: First bromodomain of BRD4 bound to inhibitor XD26 -

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Basic information

Entry
Database: PDB / ID: 5d24
TitleFirst bromodomain of BRD4 bound to inhibitor XD26
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-L26 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 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 1, 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

Downloads & links

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,6046
Polymers15,0121
Non-polymers5925
Water2,990166
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area600 Å2
ΔGint8 kcal/mol
Surface area7600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)38.910, 42.680, 78.520
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-L26 / 4-acetyl-N-[3-(2-amino-2-oxoethoxy)phenyl]-3-ethyl-5-methyl-1H-pyrrole-2-carboxamide


Mass: 343.377 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H21N3O4
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


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


Mass: 18.015 Da / Num. of mol.: 166 / 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: 2.17 Å3/Da / Density % sol: 43.36 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: ammonium acetate, (+/-)-2-Methyl-2,4-methylpentanediol, Bis-tris

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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 24, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.5→23.2 Å / Num. obs: 21647 / % possible obs: 100 % / Redundancy: 5.2 % / Rmerge(I) obs: 0.054 / Net I/σ(I): 13.1
Reflection shellResolution: 1.5→1.58 Å / Redundancy: 5.5 % / Rmerge(I) obs: 0.502 / Mean I/σ(I) obs: 3 / Num. unique all: 3101 / % possible all: 100

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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
Starting model: BRD4(1)

Resolution: 1.65→23.2 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.956 / SU B: 3.552 / SU ML: 0.066 / Cross valid method: THROUGHOUT / ESU R: 0.107 / ESU R Free: 0.101 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.2019 1593 9.8 %RANDOM
Rwork0.17326 ---
obs0.17606 14723 99.93 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 28.03 Å2
Baniso -1Baniso -2Baniso -3
1-1.78 Å2-0 Å20 Å2
2---1.52 Å2-0 Å2
3----0.25 Å2
Refinement stepCycle: 1 / Resolution: 1.65→23.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1052 0 41 166 1259
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.021127
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.4662.0021528
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1415127
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.36425.92654
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.55315196
X-RAY DIFFRACTIONr_dihedral_angle_4_deg8.296153
X-RAY DIFFRACTIONr_chiral_restr0.0870.2158
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022867
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_it0.7421.43505
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.1472.14630
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.1821.628622
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined5.4814.9685071
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: 1.65→1.693 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.248 117 -
Rwork0.208 1056 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: 12.2119 Å / Origin y: -3.5677 Å / Origin z: -9.1408 Å
111213212223313233
T0.0393 Å20.0005 Å20.0296 Å2-0.0215 Å20.0001 Å2--0.0467 Å2
L1.1384 °2-0.1408 °2-0.6144 °2-2.7401 °21.2183 °2--4.2385 °2
S-0.0917 Å °-0.0454 Å °-0.0704 Å °0.1203 Å °-0.1089 Å °0.3017 Å °0.3525 Å °-0.133 Å °0.2006 Å °

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