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- PDB-4qr5: Brd4 Bromodomain 1 complex with its novel inhibitors -

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Basic information

Entry
Database: PDB / ID: 4qr5
TitleBrd4 Bromodomain 1 complex with its novel inhibitors
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION/TRANSCRIPTION INHIBITOR / BRD4 / Bromodomain / four alpha helices / TRANSCRIPTION-TRANSCRIPTION INHIBITOR complex
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 / 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 / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / 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 II / Brdt, bromodomain, repeat I / 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 / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-BNM / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.41 Å
AuthorsXiong, B. / Cao, D.Y. / Chen, T.T. / Xu, Y.C.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Fragment-based drug discovery of 2-thiazolidinones as BRD4 inhibitors: 2. Structure-based optimization
Authors: Zhao, L. / Wang, Y. / Cao, D.Y. / Chen, T.T. / Wang, Q. / Li, Y. / Xu, Y.C. / Zhang, N. / Wang, X. / Chen, D. / Chen, L. / Chen, Y.L. / Xia, G. / Shi, Z. / Liu, Y.C. / Lin, Y. / Miao, Z. / Shen, J. / Xiong, B.
History
DepositionJun 30, 2014Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jul 1, 2015Provider: repository / Type: Initial release
Revision 1.1Mar 20, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)15,2492
Polymers14,8411
Non-polymers4081
Water2,576143
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)31.740, 47.200, 79.270
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: 14841.152 Da / Num. of mol.: 1 / Fragment: UNP residues 44-166
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: pET28a / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): codon plus / References: UniProt: O60885
#2: Chemical ChemComp-BNM / N-[3-(cyclopentylsulfamoyl)-5-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)phenyl]cyclopropanecarboxamide


Mass: 407.507 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H21N3O4S2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 143 / 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 Å3/Da / Density % sol: 38.51 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 3.6M Naformate, 10% glycerol, vapor diffusion, hanging drop, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.9793 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 27, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionHighest resolution: 1.25 Å / Num. obs: 59372 / % possible obs: 92.3 % / Observed criterion σ(I): -3 / Biso Wilson estimate: 10.14 Å2 / Rmerge(I) obs: 0.088 / Χ2: 1.024 / Net I/σ(I): 10.26
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Highest resolution (Å)Rmerge F obsRmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsRrim(I) all% possible all
1.25-1.320.5590.9341.2138191044465041.22462.3
1.32-1.410.730.7521.8924510973988990.92891.4
1.41-1.530.9010.5633.7533771912590950.65799.7
1.53-1.670.9580.345.9331259838783600.39699.7
1.67-1.870.9810.2098.8728331754875190.24399.6
1.87-2.160.9940.115.0725209666766470.11699.7
2.16-2.640.9960.06121.6121449566456480.07199.7
2.64-3.720.9980.0429.3316125433743200.04799.6
3.720.9980.0335.898978241823800.03698.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHASERphasing
PHENIX1.8.2_1309refinement
PDB_EXTRACT3.14data extraction
Blu-Icedata collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.41→30.353 Å / FOM work R set: 0.8635 / SU ML: 0.14 / σ(F): 1.33 / Phase error: 20.31 / Stereochemistry target values: MLHL
RfactorNum. reflection% reflection
Rfree0.1944 1991 8.43 %
Rwork0.1686 --
obs0.1707 23618 99.59 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 36.12 Å2 / Biso mean: 14.2 Å2 / Biso min: 5.49 Å2
Refinement stepCycle: LAST / Resolution: 1.41→30.353 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1043 0 27 143 1213
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061147
X-RAY DIFFRACTIONf_angle_d1.1641570
X-RAY DIFFRACTIONf_chiral_restr0.07162
X-RAY DIFFRACTIONf_plane_restr0.005198
X-RAY DIFFRACTIONf_dihedral_angle_d14.537451
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 27

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.41-1.42790.34041400.275715321672100
1.4279-1.44660.32671370.252214751612100
1.4466-1.46650.29371420.261614971639100
1.4665-1.48740.27621370.221492162999
1.4874-1.50960.26941460.217515211667100
1.5096-1.53320.20631370.207814861623100
1.5332-1.55830.21391390.2061491163099
1.5583-1.58520.20231400.193515361676100
1.5852-1.6140.20221390.177714581597100
1.614-1.64510.21351350.171714771612100
1.6451-1.67870.20351430.167515451688100
1.6787-1.71510.24931380.181114821620100
1.7151-1.7550.21621350.172614991634100
1.755-1.79890.20481360.16991497163399
1.7989-1.84760.19971370.17211507164499
1.8476-1.90190.22821390.16061486162599
1.9019-1.96330.1881390.161915161655100
1.9633-2.03350.17741400.157515151655100
2.0335-2.11480.17551370.162114891626100
2.1148-2.21110.16991330.150614821615100
2.2111-2.32760.17881430.153115071650100
2.3276-2.47340.14041330.153315161649100
2.4734-2.66420.1881370.163214911628100
2.6642-2.93220.19051390.177115001639100
2.9322-3.3560.2151330.17291498163199
3.356-4.22640.16691330.13251492162599
4.2264-30.35980.15861410.15361483162498

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