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- PDB-5i86: Crystal structure of the bromodomain of human CREBBP bound to the... -

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Basic information

Entry
Database: PDB / ID: 5i86
TitleCrystal structure of the bromodomain of human CREBBP bound to the benzodiazepinone G02778174
ComponentsCREB-binding protein
KeywordsPROTEIN BINDING/INHIBITOR / bromodomain inhibitor / PROTEIN BINDING-INHIBITOR complex
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-69A / THIOCYANATE ION / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.05 Å
AuthorsJayaram, H. / Poy, F. / Setser, J.W. / Bellon, S.F.
CitationJournal: Acs Med.Chem.Lett. / Year: 2016
Title: Fragment-Based Discovery of a Selective and Cell-Active Benzodiazepinone CBP/EP300 Bromodomain Inhibitor (CPI-637).
Authors: Taylor, A.M. / Cote, A. / Hewitt, M.C. / Pastor, R. / Leblanc, Y. / Nasveschuk, C.G. / Romero, F.A. / Crawford, T.D. / Cantone, N. / Jayaram, H. / Setser, J. / Murray, J. / Beresini, M.H. / ...Authors: Taylor, A.M. / Cote, A. / Hewitt, M.C. / Pastor, R. / Leblanc, Y. / Nasveschuk, C.G. / Romero, F.A. / Crawford, T.D. / Cantone, N. / Jayaram, H. / Setser, J. / Murray, J. / Beresini, M.H. / de Leon Boenig, G. / Chen, Z. / Conery, A.R. / Cummings, R.T. / Dakin, L.A. / Flynn, E.M. / Huang, O.W. / Kaufman, S. / Keller, P.J. / Kiefer, J.R. / Lai, T. / Li, Y. / Liao, J. / Liu, W. / Lu, H. / Pardo, E. / Tsui, V. / Wang, J. / Wang, Y. / Xu, Z. / Yan, F. / Yu, D. / Zawadzke, L. / Zhu, X. / Zhu, X. / Sims, R.J. / Cochran, A.G. / Bellon, S. / Audia, J.E. / Magnuson, S. / Albrecht, B.K.
History
DepositionFeb 18, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 20, 2016Provider: repository / Type: Initial release
Revision 1.1Jun 1, 2016Group: Database references
Revision 1.2Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CREB-binding protein
B: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,7857
Polymers27,9842
Non-polymers8015
Water6,936385
1
A: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,4224
Polymers13,9921
Non-polymers4303
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,3633
Polymers13,9921
Non-polymers3712
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)33.993, 42.002, 49.800
Angle α, β, γ (deg.)96.770, 109.700, 99.390
Int Tables number1
Space group name H-MP1

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Components

#1: Protein CREB-binding protein /


Mass: 13992.011 Da / Num. of mol.: 2 / Fragment: bromodomain (UNP residues 1082-1197)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CREBBP, CBP / Production host: Escherichia coli (E. coli) / References: UniProt: Q92793
#2: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-SCN / THIOCYANATE ION / Thiocyanate


Mass: 58.082 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: CNS
#4: Chemical ChemComp-69A / (4R)-N-benzyl-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-6-carboxamide


Mass: 309.362 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H19N3O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 385 / 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: 2.35 Å3/Da / Density % sol: 47.72 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop
Details: 0.2 M potassium thiocyanate, 0.1 M Bis-Tris, pH 5.5, 5% v/v ethylene glycol, 23% PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.9795 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Oct 2, 2012
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.05→50 Å / Num. obs: 108956 / % possible obs: 92.7 % / Redundancy: 2.2 % / Rmerge(I) obs: 0.032 / Χ2: 1.033 / Net I/av σ(I): 25.939 / Net I/σ(I): 13 / Num. measured all: 239112
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
1.05-1.092.10.376187.8
1.09-1.132.20.266189.4
1.13-1.182.20.193190.6
1.18-1.242.20.147191.4
1.24-1.322.20.116192.3
1.32-1.432.20.086193.3
1.43-1.572.20.059194.4
1.57-1.82.20.041195.4
1.8-2.262.20.026196.5
2.26-502.20.021195.8

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMAC5.8.0069refinement
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 3DWY

3dwy


Resolution: 1.05→40.71 Å / Cor.coef. Fo:Fc: 0.977 / Cor.coef. Fo:Fc free: 0.973 / SU B: 0.828 / SU ML: 0.019 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.027 / ESU R Free: 0.027 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.1614 5440 5 %RANDOM
Rwork0.1389 ---
obs0.14 103515 92.61 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 112.29 Å2 / Biso mean: 15.536 Å2 / Biso min: 5.47 Å2
Baniso -1Baniso -2Baniso -3
1-0.14 Å20.22 Å2-0.23 Å2
2--0.37 Å20.27 Å2
3----0.41 Å2
Refinement stepCycle: final / Resolution: 1.05→40.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1933 0 57 385 2375
Biso mean--16.48 25.11 -
Num. residues----229
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.022154
X-RAY DIFFRACTIONr_bond_other_d00.022033
X-RAY DIFFRACTIONr_angle_refined_deg1.5832.0022930
X-RAY DIFFRACTIONr_angle_other_deg0.7623.0054695
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7525246
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.59324.636110
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.25915382
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.9221514
X-RAY DIFFRACTIONr_chiral_restr0.0970.2297
X-RAY DIFFRACTIONr_gen_planes_refined0.0170.0212437
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02509
X-RAY DIFFRACTIONr_mcbond_it1.4751.179965
X-RAY DIFFRACTIONr_mcbond_other1.3871.176963
X-RAY DIFFRACTIONr_mcangle_it1.5851.7741215
X-RAY DIFFRACTIONr_rigid_bond_restr6.58334187
X-RAY DIFFRACTIONr_sphericity_free23.645567
X-RAY DIFFRACTIONr_sphericity_bonded11.45354440
LS refinement shellResolution: 1.049→1.077 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.239 388 -
Rwork0.241 7198 -
all-7586 -
obs--86.47 %

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