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- PDB-6sa3: Crystal Structure of BRD4(1) bound to inhibitor BUX4 (13) -

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Basic information

Entry
Database: PDB / ID: 6sa3
TitleCrystal Structure of BRD4(1) bound to inhibitor BUX4 (13)
ComponentsBromodomain-containing protein 4BRD4
KeywordsTRANSCRIPTION / BRD4 / BRD4(1) / INHIBITOR / BROMODOMAIN / EPIGENETIC READER PROTEIN / ACETYLATED / LYSINE / HISTONE TAIL / PROTEIN BINDING-INHIBITOR COMPLEX / BUX4 / fragment
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 / NET domain superfamily / NET domain profile. / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain, conserved site / Bromodomain signature. ...Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / NET domain superfamily / NET domain profile. / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily
Similarity search - Domain/homology
Chem-L2N / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.8 Å
AuthorsHuegle, M.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation192904750 Germany
CitationJournal: J.Med.Chem. / Year: 2020
Title: 4-Acyl Pyrroles as Dual BET-BRD7/9 Bromodomain Inhibitors Address BETi Insensitive Human Cancer Cell Lines.
Authors: Hugle, M. / Regenass, P. / Warstat, R. / Hau, M. / Schmidtkunz, K. / Lucas, X. / Wohlwend, D. / Einsle, O. / Jung, M. / Breit, B. / Gunther, S.
History
DepositionJul 16, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 9, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 16, 2020Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed ..._citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Jan 6, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3May 15, 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)15,5742
Polymers15,0991
Non-polymers4751
Water1,27971
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area6600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)27.657, 40.944, 51.412
Angle α, β, γ (deg.)90.000, 100.580, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Bromodomain-containing protein 4 / BRD4 / Protein HUNK1


Mass: 15099.380 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Production host: Escherichia coli (E. coli) / References: UniProt: O60885
#2: Chemical ChemComp-L2N / ~{N}-[2-methoxy-5-(4-methylpiperazin-1-yl)sulfonyl-phenyl]-3-methyl-4-oxidanylidene-5,6,7,8-tetrahydro-2~{H}-cyclohepta[c]pyrrole-1-carboxamide


Mass: 474.573 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H30N4O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 71 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 1.9 Å3/Da / Density % sol: 35.09 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: NaCl, MMW PEG

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.999995 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 16, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999995 Å / Relative weight: 1
ReflectionResolution: 1.57→40.94 Å / Num. obs: 15837 / % possible obs: 99.9 % / Redundancy: 6.6 % / CC1/2: 1 / Rmerge(I) obs: 0.05 / Rpim(I) all: 0.021 / Rrim(I) all: 0.054 / Net I/σ(I): 19.9 / Num. measured all: 105275 / Scaling rejects: 2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.57-1.66.71.23551897710.6880.5081.3371.699.1
8.62-40.945.60.02361310910.010.0257397.9

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation2.86 Å31.95 Å
Translation2.86 Å31.95 Å

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimless0.7.2data scaling
PHASER2.7.16phasing
PHENIXrefinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→31.814 Å / SU ML: 0.22 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 28.75
RfactorNum. reflection% reflection
Rfree0.2307 545 5.13 %
Rwork0.1929 --
obs0.1948 10615 99.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 80.32 Å2 / Biso mean: 31.5785 Å2 / Biso min: 12.9 Å2
Refinement stepCycle: final / Resolution: 1.8→31.814 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms909 0 33 76 1018
Biso mean--26.26 35.78 -
Num. residues----109
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
1.8-1.98120.32721380.26172510
1.9812-2.26780.27581430.22582489
2.2678-2.85690.23691200.22752521
2.8569-31.8140.20071440.15722550

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