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- PDB-5j0d: Crystal structure of the bromodomain of human CREBBP in complex w... -

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Basic information

Entry
Database: PDB / ID: 5j0d
TitleCrystal structure of the bromodomain of human CREBBP in complex with a benzoxazepine compound
ComponentsCREB-binding protein
KeywordsTRANSCRIPTION / histone acetyl transferase activity / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


NFE2L2 regulating ER-stress associated genes / peptide N-acetyltransferase activity / Activation of the TFAP2 (AP-2) family of transcription factors / NFE2L2 regulating inflammation associated genes / regulation of smoothened signaling pathway / histone H3K18 acetyltransferase activity / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / N-terminal peptidyl-lysine acetylation / histone H3K27 acetyltransferase activity / NFE2L2 regulates pentose phosphate pathway genes ...NFE2L2 regulating ER-stress associated genes / peptide N-acetyltransferase activity / Activation of the TFAP2 (AP-2) family of transcription factors / NFE2L2 regulating inflammation associated genes / regulation of smoothened signaling pathway / histone H3K18 acetyltransferase activity / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / N-terminal peptidyl-lysine acetylation / histone H3K27 acetyltransferase activity / NFE2L2 regulates pentose phosphate pathway genes / NFE2L2 regulating MDR associated enzymes / MRF binding / RUNX1 regulates transcription of genes involved in differentiation of myeloid cells / Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells / RUNX3 regulates NOTCH signaling / NOTCH4 Intracellular Domain Regulates Transcription / Regulation of FOXO transcriptional activity by acetylation / Regulation of gene expression by Hypoxia-inducible Factor / Nuclear events mediated by NFE2L2 / Regulation of NFE2L2 gene expression / negative regulation of transcription by RNA polymerase I / NOTCH3 Intracellular Domain Regulates Transcription / NFE2L2 regulating anti-oxidant/detoxification enzymes / TRAF6 mediated IRF7 activation / peptide-lysine-N-acetyltransferase activity / FOXO-mediated transcription of cell death genes / NFE2L2 regulating tumorigenic genes / embryonic digit morphogenesis / homeostatic process / Notch-HLH transcription pathway / protein acetylation / Formation of paraxial mesoderm / positive regulation of transforming growth factor beta receptor signaling pathway / non-canonical NF-kappaB signal transduction / Zygotic genome activation (ZGA) / stimulatory C-type lectin receptor signaling pathway / acetyltransferase activity / cellular response to nutrient levels / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / histone acetyltransferase complex / Attenuation phase / regulation of cellular response to heat / histone acetyltransferase activity / histone acetyltransferase / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / RORA activates gene expression / NPAS4 regulates expression of target genes / Regulation of lipid metabolism by PPARalpha / CD209 (DC-SIGN) signaling / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / Formation of the beta-catenin:TCF transactivating complex / protein destabilization / Heme signaling / Transcriptional activation of mitochondrial biogenesis / transcription coactivator binding / PPARA activates gene expression / Cytoprotection by HMOX1 / NOTCH1 Intracellular Domain Regulates Transcription / chromatin DNA binding / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Pre-NOTCH Transcription and Translation / Transcriptional regulation of white adipocyte differentiation / Activation of anterior HOX genes in hindbrain development during early embryogenesis / positive regulation of protein localization to nucleus / transcription corepressor activity / cellular response to UV / rhythmic process / Circadian Clock / p53 binding / TRAF3-dependent IRF activation pathway / HATs acetylate histones / protein-containing complex assembly / DNA-binding transcription factor binding / Estrogen-dependent gene expression / transcription regulator complex / RNA polymerase II-specific DNA-binding transcription factor binding / damaged DNA binding / transcription coactivator activity / response to hypoxia / nuclear body / chromatin binding / chromatin / regulation of DNA-templated transcription / SARS-CoV-2 activates/modulates innate and adaptive immune responses / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / signal transduction / positive regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
Nuclear receptor coactivator, CREB-bp-like, interlocking / Nuclear receptor coactivator, CREB-bp-like, interlocking domain superfamily / Creb binding / Zinc finger, TAZ-type / TAZ domain superfamily / TAZ zinc finger / Zinc finger TAZ-type profile. / TAZ zinc finger, present in p300 and CBP / Coactivator CBP, KIX domain / CREB-binding protein/p300, atypical RING domain ...Nuclear receptor coactivator, CREB-bp-like, interlocking / Nuclear receptor coactivator, CREB-bp-like, interlocking domain superfamily / Creb binding / Zinc finger, TAZ-type / TAZ domain superfamily / TAZ zinc finger / Zinc finger TAZ-type profile. / TAZ zinc finger, present in p300 and CBP / Coactivator CBP, KIX domain / CREB-binding protein/p300, atypical RING domain / CBP/p300-type histone acetyltransferase domain / CBP/p300, atypical RING domain superfamily / KIX domain / CREB-binding protein/p300, atypical RING domain / KIX domain profile. / CBP/p300-type histone acetyltransferase (HAT) domain profile. / Coactivator CBP, KIX domain superfamily / Histone acetyltransferase Rtt109/CBP / Histone acetylation protein / Histone acetylation protein / Zinc finger ZZ-type signature. / Zinc-binding domain, present in Dystrophin, CREB-binding protein. / Zinc finger, ZZ type / Zinc finger, ZZ-type / Zinc finger, ZZ-type superfamily / Zinc finger ZZ-type profile. / Nuclear receptor coactivator, interlocking / Bromodomain-like / Histone Acetyltransferase; Chain A / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Zinc finger, RING/FYVE/PHD-type / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-6F9 / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.05 Å
AuthorsTallant, C. / Popp, T.A. / Fedorov, O. / Siejka, P. / Picaud, S. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Bracher, F. ...Tallant, C. / Popp, T.A. / Fedorov, O. / Siejka, P. / Picaud, S. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Bracher, F. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: J.Med.Chem. / Year: 2016
Title: Development of Selective CBP/P300 Benzoxazepine Bromodomain Inhibitors.
Authors: Popp, T.A. / Tallant, C. / Rogers, C. / Fedorov, O. / Brennan, P.E. / Muller, S. / Knapp, S. / Bracher, F.
History
DepositionMar 28, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Oct 5, 2016Provider: repository / Type: Initial release
Revision 1.1Oct 19, 2016Group: Structure summary
Revision 1.2Oct 26, 2016Group: Database references
Revision 1.3Jan 10, 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: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,8915
Polymers14,2231
Non-polymers6684
Water2,288127
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area500 Å2
ΔGint7 kcal/mol
Surface area7360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)89.913, 34.848, 40.267
Angle α, β, γ (deg.)90.00, 92.32, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-1404-

HOH

21A-1415-

HOH

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Components

#1: Protein CREB-binding protein /


Mass: 14223.349 Da / Num. of mol.: 1 / Fragment: UNP residues 1081-1197
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CREBBP, CBP / Plasmid: pNIC28-Bsa4 / Cell (production host): BL21-DE3 pRARE / Production host: Escherichia coli (E. coli) / References: UniProt: Q92793, histone acetyltransferase
#2: Chemical ChemComp-6F9 / 7-(3,5-dimethoxyphenyl)-N-[(3S)-1-methylpiperidin-3-yl]-4-propanoyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-9-carboxamide


Mass: 481.584 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H35N3O5
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 127 / 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: 44.59 % / Description: Rod
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 7.5 / Details: 25% PEG3350, 0.2 M MgCl2, 0.1M BisTris pH 7.5 / PH range: 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Dec 7, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.05→29.38 Å / Num. obs: 52073 / % possible obs: 89.3 % / Redundancy: 3 % / Biso Wilson estimate: 12.642 Å2 / Rmerge(I) obs: 0.062 / Rsym value: 0.049 / Net I/av σ(I): 10.5 / Net I/σ(I): 10.5
Reflection shellResolution: 1.05→1.07 Å / Redundancy: 1.8 % / Rmerge(I) obs: 0.464 / Mean I/σ(I) obs: 2.1 / % possible all: 35.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0131refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3DWY

3dwy


Resolution: 1.05→29.38 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.964 / SU B: 0.992 / SU ML: 0.024 / Cross valid method: THROUGHOUT / ESU R: 0.032 / ESU R Free: 0.033 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.19736 2515 4.8 %RANDOM
Rwork0.17828 ---
obs0.17917 49557 89.32 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 19.092 Å2
Baniso -1Baniso -2Baniso -3
1--0.66 Å2-0 Å2-0.33 Å2
2--1.32 Å20 Å2
3----0.64 Å2
Refinement stepCycle: 1 / Resolution: 1.05→29.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms979 0 47 127 1153
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0191053
X-RAY DIFFRACTIONr_bond_other_d0.0010.021000
X-RAY DIFFRACTIONr_angle_refined_deg1.5851.9781424
X-RAY DIFFRACTIONr_angle_other_deg0.96132307
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8065116
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.51624.70651
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.54715179
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.889156
X-RAY DIFFRACTIONr_chiral_restr0.0940.2145
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0211232
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02234
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_it0.8881.391467
X-RAY DIFFRACTIONr_mcbond_other0.8761.386466
X-RAY DIFFRACTIONr_mcangle_it1.4322.082582
X-RAY DIFFRACTIONr_mcangle_other1.4342.086583
X-RAY DIFFRACTIONr_scbond_it1.5241.624586
X-RAY DIFFRACTIONr_scbond_other1.5231.624586
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.4312.35843
X-RAY DIFFRACTIONr_long_range_B_refined4.82612.6991345
X-RAY DIFFRACTIONr_long_range_B_other4.61212.0841280
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.05→1.078 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.238 88 -
Rwork0.29 1526 -
obs--37.76 %
Refinement TLS params.Method: refined / Origin x: 12.3359 Å / Origin y: 25.9817 Å / Origin z: 12.6126 Å
111213212223313233
T0.0145 Å2-0.0089 Å2-0.0065 Å2-0.03 Å2-0.0004 Å2--0.0071 Å2
L0.1111 °2-0.0151 °20.2523 °2-0.7804 °2-0.1733 °2--0.7809 °2
S0.0001 Å °-0.0117 Å °-0.0136 Å °-0.0556 Å °0.0441 Å °0.0472 Å °-0.0175 Å °0.033 Å °-0.0442 Å °

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