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- PDB-5lrq: BRD4 in complex with ERK5 inhibitor XMD8-92 -

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Basic information

Entry
Database: PDB / ID: 5lrq
TitleBRD4 in complex with ERK5 inhibitor XMD8-92
ComponentsBromodomain-containing protein 4BRD4
KeywordsTRANSCRIPTION / BRD4 / BROMODOMAIN CONTAINING PROTEIN 4 / ERK5 / Inhibitor
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 / transcription coregulator activity ...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 / transcription coregulator activity / positive regulation of transcription elongation by RNA polymerase II / 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-like / Histone Acetyltransferase; Chain A ...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-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-4WG / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsMartin, M.P. / Noble, M.E.M.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Cancer Research UK United Kingdom
CitationJournal: Eur.J.Med.Chem. / Year: 2019
Title: Identification of a novel orally bioavailable ERK5 inhibitor with selectivity over p38 alpha and BRD4.
Authors: Myers, S.M. / Miller, D.C. / Molyneux, L. / Arasta, M. / Bawn, R.H. / Blackburn, T.J. / Cook, S.J. / Edwards, N. / Endicott, J.A. / Golding, B.T. / Griffin, R.J. / Hammonds, T. / Hardcastle, ...Authors: Myers, S.M. / Miller, D.C. / Molyneux, L. / Arasta, M. / Bawn, R.H. / Blackburn, T.J. / Cook, S.J. / Edwards, N. / Endicott, J.A. / Golding, B.T. / Griffin, R.J. / Hammonds, T. / Hardcastle, I.R. / Harnor, S.J. / Heptinstall, A.B. / Lochhead, P.A. / Martin, M.P. / Martin, N.C. / Newell, D.R. / Owen, P.J. / Pang, L.C. / Reuillon, T. / Rigoreau, L.J.M. / Thomas, H.D. / Tucker, J.A. / Wang, L.Z. / Wong, A.C. / Noble, M.E.M. / Wedge, S.R. / Cano, C.
History
DepositionAug 19, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 30, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 4, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 17, 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)17,3902
Polymers16,9151
Non-polymers4751
Water2,054114
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area7610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.923, 53.923, 89.320
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

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Components

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


Mass: 16915.332 Da / Num. of mol.: 1 / Fragment: UNP residues 42-163
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: O60885
#2: Chemical ChemComp-4WG / 2-{[2-ethoxy-4-(4-hydroxypiperidin-1-yl)phenyl]amino}-5,11-dimethyl-5,11-dihydro-6H-pyrimido[4,5-b][1,4]benzodiazepin-6-one


Mass: 474.555 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H30N6O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 114 / 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: 2.22 Å3/Da / Density % sol: 44.5 %
Crystal growTemperature: 278 K / Method: vapor diffusion, sitting drop / pH: 7
Details: BRD4 10mg/ml 30w/v Jeffamine ED-2001 0.1M HEPES pH7.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.969 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Apr 22, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.969 Å / Relative weight: 1
ReflectionResolution: 1.7→46.7 Å / Num. obs: 17138 / % possible obs: 100 % / Redundancy: 10.3 % / CC1/2: 1 / Rmerge(I) obs: 0.081 / Net I/σ(I): 14.4
Reflection shellResolution: 1.7→1.73 Å / Redundancy: 10.4 % / Rmerge(I) obs: 0.96 / Mean I/σ(I) obs: 2.3 / CC1/2: 0.91 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0155refinement
xia2data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OSS

2oss


Resolution: 1.7→46.7 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.947 / SU B: 3.376 / SU ML: 0.1 / Cross valid method: THROUGHOUT / ESU R: 0.102 / ESU R Free: 0.108 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23267 862 5 %RANDOM
Rwork0.18667 ---
obs0.1891 16240 99.99 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 29.126 Å2
Baniso -1Baniso -2Baniso -3
1--1.54 Å2-0.77 Å2-0 Å2
2---1.54 Å20 Å2
3---4.98 Å2
Refinement stepCycle: 1 / Resolution: 1.7→46.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1015 0 35 114 1164
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0191083
X-RAY DIFFRACTIONr_bond_other_d0.0040.021026
X-RAY DIFFRACTIONr_angle_refined_deg1.8881.9621476
X-RAY DIFFRACTIONr_angle_other_deg1.052.9612370
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0785121
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.4525.76952
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.34415187
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.004152
X-RAY DIFFRACTIONr_chiral_restr0.1310.2151
X-RAY DIFFRACTIONr_gen_planes_refined0.0130.0211214
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02244
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.9482.595487
X-RAY DIFFRACTIONr_mcbond_other2.8862.587486
X-RAY DIFFRACTIONr_mcangle_it4.1213.864607
X-RAY DIFFRACTIONr_mcangle_other4.1183.877608
X-RAY DIFFRACTIONr_scbond_it3.472.947594
X-RAY DIFFRACTIONr_scbond_other3.4672.944595
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.5144.273870
X-RAY DIFFRACTIONr_long_range_B_refined7.65630.6721328
X-RAY DIFFRACTIONr_long_range_B_other7.64130.2281303
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.7→1.744 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.303 47 -
Rwork0.318 1190 -
obs--100 %

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