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- PDB-8pxa: N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH (S)-5-(1-((1-(1-isoprop... -

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Basic information

Entry
Database: PDB / ID: 8pxa
TitleN-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH (S)-5-(1-((1-(1-isopropylpiperidine-4-carbonyl)piperidin-3-yl)methyl)-1H-benzo[d]imidazol-2-yl)-1,3-dimethylpyridin-2(1H)-one
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION / INHIBITOR / HISTONE / EPIGENETIC READER / BROMODOMAIN / BRD4 / BROMODOMAIN CONTAINING PROTEIN 4 / ANTAGONIST
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 / chromatin / 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-I0Z / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.3 Å
AuthorsChung, C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2023
Title: Structure-Guided Design of a Domain-Selective Bromodomain and Extra Terminal N-Terminal Bromodomain Chemical Probe.
Authors: Bradley, E. / Fusani, L. / Chung, C.W. / Craggs, P.D. / Demont, E.H. / Humphreys, P.G. / Mitchell, D.J. / Phillipou, A. / Rioja, I. / Shah, R.R. / Wellaway, C.R. / Prinjha, R.K. / Palmer, D. ...Authors: Bradley, E. / Fusani, L. / Chung, C.W. / Craggs, P.D. / Demont, E.H. / Humphreys, P.G. / Mitchell, D.J. / Phillipou, A. / Rioja, I. / Shah, R.R. / Wellaway, C.R. / Prinjha, R.K. / Palmer, D.S. / Kerr, W.J. / Reid, M. / Wall, I.D. / Cookson, R.
History
DepositionJul 22, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 18, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Dec 27, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
AAA: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,5892
Polymers15,0991
Non-polymers4901
Water3,765209
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 area7670 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.845, 47.236, 58.974
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-I0Z / 1,3-dimethyl-5-[1-[[(3~{S})-1-(1-propan-2-ylpiperidin-4-yl)carbonylpiperidin-3-yl]methyl]benzimidazol-2-yl]pyridin-2-one


Mass: 489.652 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H39N5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 209 / 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: 2.07 Å3/Da / Density % sol: 40.53 %
Crystal growTemperature: 277 K / Method: vapor diffusion / Details: 0.1M Tris pH8.5, 12% w/v PEG4K

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.979507 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 5, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979507 Å / Relative weight: 1
ReflectionResolution: 1.3→58.97 Å / Num. obs: 31016 / % possible obs: 98.5 % / Redundancy: 5.8 % / CC1/2: 0.999 / Rmerge(I) obs: 0.06 / Net I/σ(I): 13.8
Reflection shellResolution: 1.3→1.37 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.475 / Mean I/σ(I) obs: 1.9 / Num. unique obs: 4029 / CC1/2: 0.751 / % possible all: 90.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0257refinement
XDSdata reduction
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.3→32.544 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.949 / SU B: 0.936 / SU ML: 0.04 / Cross valid method: FREE R-VALUE / ESU R: 0.061 / ESU R Free: 0.061
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2175 1588 5.129 %
Rwork0.1984 29371 -
all0.199 --
obs-30959 98.304 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL PLUS MASK
Displacement parametersBiso mean: 17.014 Å2
Baniso -1Baniso -2Baniso -3
1--0.18 Å20 Å2-0 Å2
2--0.009 Å2-0 Å2
3---0.17 Å2
Refinement stepCycle: LAST / Resolution: 1.3→32.544 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1046 0 36 209 1291
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0131137
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171046
X-RAY DIFFRACTIONr_angle_refined_deg1.1931.6621556
X-RAY DIFFRACTIONr_angle_other_deg1.2031.6252458
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8875130
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.4532556
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.91315198
X-RAY DIFFRACTIONr_dihedral_angle_4_deg8.102153
X-RAY DIFFRACTIONr_chiral_restr0.0620.2144
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021326
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02211
X-RAY DIFFRACTIONr_nbd_refined0.1890.2243
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1650.2924
X-RAY DIFFRACTIONr_nbtor_refined0.1720.2541
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0780.2386
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1280.2142
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.0580.28
X-RAY DIFFRACTIONr_nbd_other0.1520.253
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.120.231
X-RAY DIFFRACTIONr_mcbond_it0.8552.127511
X-RAY DIFFRACTIONr_mcbond_other0.8492.123510
X-RAY DIFFRACTIONr_mcangle_it1.3984.785642
X-RAY DIFFRACTIONr_mcangle_other1.3934.79642
X-RAY DIFFRACTIONr_scbond_it1.2762.309626
X-RAY DIFFRACTIONr_scbond_other1.2752.309627
X-RAY DIFFRACTIONr_scangle_it2.0585.064913
X-RAY DIFFRACTIONr_scangle_other2.0575.065914
X-RAY DIFFRACTIONr_lrange_it4.63421.411387
X-RAY DIFFRACTIONr_lrange_other4.17420.2991328
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.3-1.3340.298940.2911831X-RAY DIFFRACTION84.282
1.334-1.370.2831140.2651980X-RAY DIFFRACTION94.3243
1.37-1.410.2671160.2422027X-RAY DIFFRACTION98.3479
1.41-1.4530.2331050.2262014X-RAY DIFFRACTION99.8586
1.453-1.5010.182950.2091939X-RAY DIFFRACTION99.9018
1.501-1.5530.196970.1961904X-RAY DIFFRACTION100
1.553-1.6120.197960.1971821X-RAY DIFFRACTION99.9479
1.612-1.6780.2111080.2031746X-RAY DIFFRACTION99.9461
1.678-1.7520.239630.2011705X-RAY DIFFRACTION100
1.752-1.8370.243750.21623X-RAY DIFFRACTION99.9411
1.837-1.9360.238960.2011524X-RAY DIFFRACTION99.9383
1.936-2.0540.211770.1951480X-RAY DIFFRACTION99.9358
2.054-2.1950.204720.1831376X-RAY DIFFRACTION100
2.195-2.370.185980.1751270X-RAY DIFFRACTION100
2.37-2.5950.229610.1941188X-RAY DIFFRACTION100
2.595-2.90.204700.2041071X-RAY DIFFRACTION100
2.9-3.3450.199600.181959X-RAY DIFFRACTION100
3.345-4.0880.203410.175842X-RAY DIFFRACTION99.8869
4.088-5.7460.27350.19660X-RAY DIFFRACTION100
5.746-32.5440.227150.227411X-RAY DIFFRACTION99.5327

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