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- PDB-6rwj: Crystal Structure of BRD4(1) bound to inhibitor BUG0 (6) -

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Basic information

Entry
Database: PDB / ID: 6rwj
TitleCrystal Structure of BRD4(1) bound to inhibitor BUG0 (6)
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION / BRD4 / BRD4(1) / INHIBITOR / BROMODOMAIN / EPIGENETIC READER PROTEIN / ACETYLATED / LYSINE / HISTONE TAIL / PROTEIN BINDING-INHIBITOR COMPLEX / BUG0 / 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 / 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
Chem-KLK / 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
DepositionJun 5, 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)15,3202
Polymers15,0991
Non-polymers2201
Water4,594255
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 area7580 Å2
MethodPISA
Unit cell
Length a, b, c (Å)37.645, 44.173, 78.518
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 / Fragment: FIRST BROMODOMAIN (UNP RESIDUES 44-168)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: pNIC28-bsa4 / Details (production host): pNIC28-bsa4::BRD4 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: O60885
#2: Chemical ChemComp-KLK / ~{N},3-dimethyl-4-oxidanylidene-5,6,7,8-tetrahydro-2~{H}-cyclohepta[c]pyrrole-1-carboxamide


Mass: 220.268 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H16N2O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 255 / 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: 2.16 Å3/Da / Density % sol: 43.1 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: TRIS, PEG3350, NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.00003 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Nov 30, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00003 Å / Relative weight: 1
ReflectionResolution: 1.2→44.17 Å / Num. obs: 46538 / % possible obs: 98.3 % / Redundancy: 8.3 % / Biso Wilson estimate: 8.35 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.092 / Rpim(I) all: 0.032 / Rrim(I) all: 0.098 / Net I/σ(I): 14
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
1.2-1.23.30.47918730.6940.2850.56481.1
6.3-44.178.20.0853520.9910.030.09199.5

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation3.52 Å39.26 Å

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Processing

Software
NameVersionClassificationNB
PHENIXrefinement
XDSdata reduction
Aimless0.3.11data scaling
PHASER2.7.16phasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4LYW

4lyw


Resolution: 1.4→39.259 Å / SU ML: 0.1 / Cross valid method: THROUGHOUT / σ(F): 1.41 / Phase error: 15.45
RfactorNum. reflection% reflection
Rfree0.181 2613 9.86 %
Rwork0.1559 --
obs0.1584 26492 99.89 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 51.15 Å2 / Biso mean: 13.0272 Å2 / Biso min: 3.46 Å2
Refinement stepCycle: final / Resolution: 1.4→39.259 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1060 0 16 273 1349
Biso mean--5.02 23.33 -
Num. residues----127
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 19

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.4-1.42550.21291310.171212551386100
1.4255-1.45290.18121410.174612401381100
1.4529-1.48250.18191300.161612361366100
1.4825-1.51480.20621140.164212391353100
1.5148-1.550.17521320.159312451377100
1.55-1.58880.18631330.162212481381100
1.5888-1.63170.20341520.159312371389100
1.6317-1.67980.19881380.154312131351100
1.6798-1.7340.18251170.157312531370100
1.734-1.7960.18881440.162412441388100
1.796-1.86790.17361200.151812761396100
1.8679-1.95290.17951290.157712491378100
1.9529-2.05580.171540.152412291383100
2.0558-2.18460.18211500.144512521402100
2.1846-2.35330.16651440.150712561400100
2.3533-2.59010.19251290.168112751404100
2.5901-2.96470.17521390.153712851424100
2.9647-3.73480.17931460.14512981444100
3.7348-39.27440.17581700.15731349151999

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