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- PDB-5cy9: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 5cy9
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 / BROMODOMAIN BINDING INHIBITOR / 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-E0A / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 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 30, 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 1.3Nov 8, 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 / citation / database_2 / diffrn_radiation_wavelength / pdbx_initial_refinement_model / 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)17,3786
Polymers16,7671
Non-polymers6115
Water2,702150
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area200 Å2
ΔGint-1 kcal/mol
Surface area8190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.050, 54.050, 50.690
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number144
Space group name H-MP31

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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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-E0A / N-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)butane-1-sulfonamide


Mass: 332.417 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H20N2O3S
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 150 / 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: 2.57 Å3/Da / Density % sol: 52.13 %
Description: THE ENTRY CONTAINS FRIEDEL PAIRS IN F_PLUS/MINUS COLUMNS.
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.8
Details: 20% PEG3350, 0.2M NaCl, 0.1M HEPES, 10% EtGhly,pH 7.8

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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: 1.55→46.81 Å / Num. obs: 21754 / % possible obs: 90.5 % / Redundancy: 7.8 % / CC1/2: 0.999 / Rmerge(I) obs: 0.064 / Rpim(I) all: 0.023 / Net I/σ(I): 14.7 / Num. measured all: 169111 / Scaling rejects: 80
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
1.55-1.585.90.3563.2653811090.9340.15595.2
8.49-46.8110.60.05833.615651480.9950.01899.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0131refinement
Aimless0.5.9data scaling
PDB_EXTRACT3.15data extraction
MOSFLMdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3MXF

3mxf


Resolution: 1.55→46.81 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.956 / SU B: 1.391 / SU ML: 0.05 / Cross valid method: THROUGHOUT / ESU R: 0.077 / ESU R Free: 0.081 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.19788 1192 5.5 %RANDOM
Rwork0.16317 ---
obs0.16501 20541 90.52 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 19.902 Å2
Baniso -1Baniso -2Baniso -3
1--0.33 Å2-0.17 Å20 Å2
2---0.33 Å2-0 Å2
3---1.08 Å2
Refinement stepCycle: LAST / Resolution: 1.55→46.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1091 0 41 150 1282
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.021169
X-RAY DIFFRACTIONr_bond_other_d0.0040.021125
X-RAY DIFFRACTIONr_angle_refined_deg1.51221588
X-RAY DIFFRACTIONr_angle_other_deg1.0873.0062598
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0125132
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.06125.53656
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.30715201
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.072154
X-RAY DIFFRACTIONr_chiral_restr0.0740.2166
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0211289
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02263
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_it1.2131.699525
X-RAY DIFFRACTIONr_mcbond_other1.2131.692524
X-RAY DIFFRACTIONr_mcangle_it1.9392.54655
X-RAY DIFFRACTIONr_mcangle_other1.9372.548656
X-RAY DIFFRACTIONr_scbond_it2.0721.992644
X-RAY DIFFRACTIONr_scbond_other2.0721.992644
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.3552.867933
X-RAY DIFFRACTIONr_long_range_B_refined5.07514.8311515
X-RAY DIFFRACTIONr_long_range_B_other5.07314.8591516
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.55→1.59 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.235 75 -
Rwork0.242 1601 -
obs--95.34 %

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