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- PDB-5a5s: NN-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH 5-5-methoxypyridin-3-y... -

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Basic information

Entry
Database: PDB / ID: 5a5s
TitleNN-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH 5-5-methoxypyridin-3-yl-3- methyl-8-piperidin-4-ylamino-1,2-dihydro-1,7-naphthyridin-2-one
ComponentsBROMODOMAIN-CONTAINING PROTEIN 4
KeywordsHYDROLASE / 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 / RNA polymerase II CTD heptapeptide repeat kinase activity / histone reader 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 / RNA polymerase II CTD heptapeptide repeat kinase activity / histone reader 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 I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain-like ...Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / 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-NP8 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.36 Å
AuthorsChung, C. / Bamborough, P. / Demont, E.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Fragment-Based Discovery of Low-Micromolar Atad2 Bromodomain Inhibitors.
Authors: Demont, E.H. / Chung, C. / Furze, R.C. / Grandi, P. / Michon, A. / Wellaway, C. / Barrett, N. / Bridges, A.M. / Craggs, P.D. / Diallo, H. / Dixon, D.P. / Douault, C. / Emmons, A.J. / Jones, ...Authors: Demont, E.H. / Chung, C. / Furze, R.C. / Grandi, P. / Michon, A. / Wellaway, C. / Barrett, N. / Bridges, A.M. / Craggs, P.D. / Diallo, H. / Dixon, D.P. / Douault, C. / Emmons, A.J. / Jones, E.J. / Karamshi, B.V. / Locke, K. / Mitchell, D.J. / Mouzon, B.H. / Prinjha, R.K. / Roberts, A.D. / Sheppard, R.J. / Watson, R.J. / Bamborough, P.
History
DepositionJun 20, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 22, 2015Provider: repository / Type: Initial release
Revision 1.1Aug 5, 2015Group: Database references
Revision 1.2May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)15,5283
Polymers15,1001
Non-polymers4272
Water2,450136
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)39.390, 49.390, 59.230
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein BROMODOMAIN-CONTAINING PROTEIN 4 / PROTEIN HUNK1 / HUMAN BRD4


Mass: 15100.431 Da / Num. of mol.: 1 / Fragment: N-TERMINAL BROMODOMAIN, UNP RESIDUES 44-168
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: O60885
#2: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-NP8 / 5-(5-methoxypyridin-3-yl)-3-methyl-8-[(piperidin-4-yl)amino]-1,2-dihydro-1,7-naphthyridin-2-one


Mass: 365.429 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H23N5O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 136 / 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: 1.91 Å3/Da / Density % sol: 35.52 % / Description: NONE
Crystal growDetails: 0.2NAF, 20% PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 17, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.36→39.39 Å / Num. obs: 24744 / % possible obs: 98.1 % / Observed criterion σ(I): 2 / Redundancy: 3 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 12.6
Reflection shellResolution: 1.36→1.44 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.1 / Mean I/σ(I) obs: 7.6 / % possible all: 98.9

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 1.36→37.93 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.937 / SU B: 1.844 / SU ML: 0.041 / Cross valid method: THROUGHOUT / ESU R: 0.076 / ESU R Free: 0.07 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.21779 1261 5.1 %RANDOM
Rwork0.20874 ---
obs0.20921 23440 97.56 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 11.079 Å2
Baniso -1Baniso -2Baniso -3
1-0.1 Å20 Å20 Å2
2--0.22 Å20 Å2
3----0.32 Å2
Refinement stepCycle: LAST / Resolution: 1.36→37.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1057 0 31 136 1224
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.021150
X-RAY DIFFRACTIONr_bond_other_d0.0010.02799
X-RAY DIFFRACTIONr_angle_refined_deg0.971.9711568
X-RAY DIFFRACTIONr_angle_other_deg0.78531970
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.745134
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.2932655
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.81515206
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.835153
X-RAY DIFFRACTIONr_chiral_restr0.0540.2163
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0211240
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02211
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.363→1.398 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.233 76 -
Rwork0.21 1606 -
obs--97.9 %
Refinement TLS params.Method: refined / Origin x: -6.8607 Å / Origin y: -8.3685 Å / Origin z: 17.9035 Å
111213212223313233
T0.0017 Å2-0.0006 Å2-0.0016 Å2-0.0063 Å20.0011 Å2--0.0102 Å2
L0.4337 °20.2348 °20.2387 °2-0.2214 °20.2177 °2--0.5644 °2
S-0.0131 Å °0.0441 Å °-0.0042 Å °0.001 Å °0.0351 Å °-0.0036 Å °0.0022 Å °0.0227 Å °-0.0219 Å °

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