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- PDB-5ctl: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 5ctl
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with benzo[cd]indol-2(1H)-one ligand
ComponentsBromodomain-containing protein 4
KeywordsSIGNALING PROTEIN/INHIBITOR / BRD4 / Bromodomain / Four Alpha Helices / SIGNALING PROTEIN-INHIBITOR complex
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-EB9 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.51 Å
AuthorsZhang, Y. / Song, M. / Liu, Z. / Xue, X. / Xu, Y.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Discovery of Benzo[cd]indol-2(1H)-ones as Potent and Specific BET Bromodomain Inhibitors: Structure-Based Virtual Screening, Optimization, and Biological Evaluation
Authors: Xue, X. / Zhang, Y. / Liu, Z. / Song, M. / Xing, Y. / Xiang, Q. / Wang, Z. / Tu, Z. / Zhou, Y. / Ding, K. / Xu, Y.
History
DepositionJul 24, 2015Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jan 13, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 27, 2016Group: Data collection / Database references
Revision 1.2Mar 9, 2016Group: Database references
Revision 1.3Mar 20, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / diffrn_radiation_wavelength / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)17,1202
Polymers16,7671
Non-polymers3521
Water18010
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area8550 Å2
Unit cell
Length a, b, c (Å)34.640, 47.340, 77.960
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: 16767.326 Da / Num. of mol.: 1 / Fragment: N-TERMINAL BROMODOMAIN, UNP residues 44-168
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: pET24a / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: O60885
#2: Chemical ChemComp-EB9 / N-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)benzenesulfonamide


Mass: 352.407 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H16N2O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 10 / 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: 1.92 Å3/Da / Density % sol: 35.86 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 20% PEG3350, 0.2M NaNO3, 0.1M HEPES, 10% EtGhly,pH 7.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Type: OTHER / Wavelength: 0.97852 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Jun 22, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97852 Å / Relative weight: 1
ReflectionResolution: 2.51→47.34 Å / Num. obs: 4435 / % possible obs: 94 % / Redundancy: 7.5 % / CC1/2: 0.993 / Rmerge(I) obs: 0.121 / Rpim(I) all: 0.045 / Net I/σ(I): 10.3 / Num. measured all: 33047 / Scaling rejects: 94
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allCC1/2Rpim(I) all% possible all
2.51-2.617.40.2465.737004970.9820.09197.7
9.05-47.348.20.09116.211011350.9980.03199.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0131refinement
Aimless0.5.9data scaling
PDB_EXTRACT3.15data extraction
MOSFLMdata reduction
MOLREPphasing
RefinementResolution: 2.51→40.46 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.93 / SU B: 11.76 / SU ML: 0.246 / Cross valid method: THROUGHOUT / ESU R Free: 0.309 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22687 195 4.4 %RANDOM
Rwork0.20132 ---
obs0.20262 4206 93.46 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 33.561 Å2
Baniso -1Baniso -2Baniso -3
1-9.14 Å20 Å20 Å2
2---4.15 Å20 Å2
3----4.99 Å2
Refinement stepCycle: LAST / Resolution: 2.51→40.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1115 0 25 10 1150
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0191179
X-RAY DIFFRACTIONr_bond_other_d0.0030.021113
X-RAY DIFFRACTIONr_angle_refined_deg1.5671.9791608
X-RAY DIFFRACTIONr_angle_other_deg1.0033.0052566
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.595132
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.3842558
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.16915200
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.315154
X-RAY DIFFRACTIONr_chiral_restr0.0780.2165
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0211313
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02283
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_it1.9073.231531
X-RAY DIFFRACTIONr_mcbond_other1.9093.229530
X-RAY DIFFRACTIONr_mcangle_it3.1914.837662
X-RAY DIFFRACTIONr_mcangle_other3.1894.839663
X-RAY DIFFRACTIONr_scbond_it1.9083.406648
X-RAY DIFFRACTIONr_scbond_other1.9073.404649
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.3145.014947
X-RAY DIFFRACTIONr_long_range_B_refined5.03524.3691349
X-RAY DIFFRACTIONr_long_range_B_other5.03424.3781349
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.51→2.575 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.328 13 -
Rwork0.278 299 -
obs--97.5 %

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