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- PDB-6s6k: Crystal Structure of BRD4(1) bound to inhibitor BUX2 (9) -

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Basic information

Entry
Database: PDB / ID: 6s6k
TitleCrystal Structure of BRD4(1) bound to inhibitor BUX2 (9)
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION / BRD4 / BRD4(1) / INHIBITOR / BROMODOMAIN / EPIGENETIC READER PROTEIN / ACETYLATED / LYSINE / HISTONE TAIL / PROTEIN BINDING-INHIBITOR COMPLEX / BUX0
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, conserved site ...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, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily
Similarity search - Domain/homology
(R,R)-2,3-BUTANEDIOL / Chem-KXK / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.4 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 3, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 9, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 16, 2020Group: Database references / Structure summary / Category: audit_author / 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 1.3Jan 24, 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

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,9336
Polymers15,0991
Non-polymers8345
Water3,135174
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area880 Å2
ΔGint4 kcal/mol
Surface area7760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.454, 46.808, 57.299
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: 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-KXK / ~{N}-[5-(azepan-1-ylsulfonyl)-2-methoxy-phenyl]-3-methyl-4-oxidanylidene-5,6,7,8-tetrahydro-2~{H}-cyclohepta[c]pyrrole-1-carboxamide


Mass: 473.585 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H31N3O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-BU3 / (R,R)-2,3-BUTANEDIOL


Mass: 90.121 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C4H10O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 174 / 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: 1.84 Å3/Da / Density % sol: 33.18 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: HEPES, PEG3350, NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.000031 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: May 5, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.000031 Å / Relative weight: 1
ReflectionResolution: 1.31→47.04 Å / Num. obs: 27833 / % possible obs: 99.6 % / Redundancy: 12.8 % / CC1/2: 1 / Rmerge(I) obs: 0.066 / Rpim(I) all: 0.019 / Rrim(I) all: 0.069 / Net I/σ(I): 19.5 / Num. measured all: 356383 / 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
1.31-1.3311.21.5381497913340.5490.4681.6111.697.1
7.04-47.0410.60.033239322610.010.03456.999.8

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation3.05 Å36.25 Å
Translation3.05 Å36.25 Å

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Processing

Software
NameVersionClassificationNB
PHENIXrefinement
XDSdata reduction
Aimless0.7.1data scaling
PHASER2.7.16phasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4LYW

4lyw


Resolution: 1.4→36.25 Å / SU ML: 0.12 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 15.37
RfactorNum. reflection% reflection
Rfree0.1578 1169 5.18 %
Rwork0.1225 --
obs0.1243 22586 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 47.39 Å2 / Biso mean: 15.0399 Å2 / Biso min: 7.52 Å2
Refinement stepCycle: final / Resolution: 1.4→36.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1054 0 63 191 1308
Biso mean--19.75 27.59 -
Num. residues----127
LS refinement shell

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

Resolution (Å)Highest resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
1.4-1.46380.23281462644
1.4638-1.54090.18241450.11932626
1.5409-1.63750.15461520.1122620
1.6375-1.76390.1841620.10922637
1.7639-1.94140.14131450.10562649
1.9414-2.22230.15331360.10542689
2.2223-2.79970.14921340.12982712
2.79970.15121490.1322840

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