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- PDB-5dbm: Crystal structure of the CBP bromodomain in complex with CPI703 -

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Basic information

Entry
Database: PDB / ID: 5dbm
TitleCrystal structure of the CBP bromodomain in complex with CPI703
ComponentsCREB-binding protein
KeywordsPROTEIN BINDING / bromodomain / inhibitor / epigenetics / chromatin
Function / homology
Function and homology information


peptide lactyltransferase (CoA-dependent) activity / NFE2L2 regulating ER-stress associated genes / protein N-acetyltransferase activity / Activation of the TFAP2 (AP-2) family of transcription factors / NFE2L2 regulating inflammation associated genes / N-terminal peptidyl-lysine acetylation / regulation of smoothened signaling pathway / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / NFE2L2 regulates pentose phosphate pathway genes / NFE2L2 regulating MDR associated enzymes ...peptide lactyltransferase (CoA-dependent) activity / NFE2L2 regulating ER-stress associated genes / protein N-acetyltransferase activity / Activation of the TFAP2 (AP-2) family of transcription factors / NFE2L2 regulating inflammation associated genes / N-terminal peptidyl-lysine acetylation / regulation of smoothened signaling pathway / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / 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 FOXO transcriptional activity by acetylation / Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells / RUNX3 regulates NOTCH signaling / Nuclear events mediated by NFE2L2 / NOTCH4 Intracellular Domain Regulates Transcription / Regulation of NFE2L2 gene expression / Regulation of gene expression by Hypoxia-inducible Factor / NOTCH3 Intracellular Domain Regulates Transcription / negative regulation of transcription by RNA polymerase I / TRAF6 mediated IRF7 activation / NFE2L2 regulating tumorigenic genes / NFE2L2 regulating anti-oxidant/detoxification enzymes / protein-lysine-acetyltransferase activity / embryonic digit morphogenesis / protein acetylation / homeostatic process / Notch-HLH transcription pathway / Formation of paraxial mesoderm / positive regulation of transforming growth factor beta receptor signaling pathway / histone acetyltransferase activity / acetyltransferase activity / FOXO-mediated transcription of cell death genes / stimulatory C-type lectin receptor signaling pathway / Zygotic genome activation (ZGA) / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / histone acetyltransferase complex / canonical NF-kappaB signal transduction / cellular response to nutrient levels / Attenuation phase / positive regulation of double-strand break repair via homologous recombination / histone H4K16 acetyltransferase activity / histone H3K56 acetyltransferase activity / histone H3K23 acetyltransferase activity / histone H2AK5 acetyltransferase activity / histone H2AK9 acetyltransferase activity / histone H2BK5 acetyltransferase activity / histone H2BK12 acetyltransferase activity / histone H3K4 acetyltransferase activity / histone H3K27 acetyltransferase activity / histone H3K36 acetyltransferase activity / histone H3K122 acetyltransferase activity / histone H3K18 acetyltransferase activity / histone H3K9 acetyltransferase activity / histone H3K14 acetyltransferase activity / histone H4K5 acetyltransferase activity / histone H4K8 acetyltransferase activity / histone H4K12 acetyltransferase activity / regulation of cellular response to heat / histone acetyltransferase / : / Regulation of lipid metabolism by PPARalpha / NPAS4 regulates expression of target genes / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / Transcriptional and post-translational regulation of MITF-M expression and activity / CD209 (DC-SIGN) signaling / BMAL1:CLOCK,NPAS2 activates circadian expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / Formation of the beta-catenin:TCF transactivating complex / Heme signaling / Transcriptional activation of mitochondrial biogenesis / transcription coactivator binding / PPARA activates gene expression / protein destabilization / Cytoprotection by HMOX1 / Evasion by RSV of host interferon responses / chromatin DNA binding / Transcriptional regulation of white adipocyte differentiation / Pre-NOTCH Transcription and Translation / positive regulation of protein localization to nucleus / NOTCH1 Intracellular Domain Regulates Transcription / tau protein binding / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Activation of anterior HOX genes in hindbrain development during early embryogenesis / transcription corepressor activity / cellular response to UV / p53 binding / rhythmic process / : / HATs acetylate histones / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / TRAF3-dependent IRF activation pathway / protein-containing complex assembly / DNA-binding transcription factor binding / transcription regulator complex / Estrogen-dependent gene expression / RNA polymerase II-specific DNA-binding transcription factor binding
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 / : / Histone acetyltransferase p300-like, PHD 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 / : / Histone acetyltransferase p300-like, PHD domain / 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. / Histone acetyltransferase Rtt109/CBP / Histone acetylation protein / Histone acetylation protein / Coactivator CBP, KIX domain superfamily / 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-58N / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.86 Å
AuthorsSetser, J.W. / Poy, F. / Bellon, S.F.
CitationJournal: J.Biol.Chem. / Year: 2016
Title: Regulatory T Cell Modulation by CBP/EP300 Bromodomain Inhibition.
Authors: Ghosh, S. / Taylor, A. / Chin, M. / Huang, H.R. / Conery, A.R. / Mertz, J.A. / Salmeron, A. / Dakle, P.J. / Mele, D. / Cote, A. / Jayaram, H. / Setser, J.W. / Poy, F. / Hatzivassiliou, G. / ...Authors: Ghosh, S. / Taylor, A. / Chin, M. / Huang, H.R. / Conery, A.R. / Mertz, J.A. / Salmeron, A. / Dakle, P.J. / Mele, D. / Cote, A. / Jayaram, H. / Setser, J.W. / Poy, F. / Hatzivassiliou, G. / DeAlmeida-Nagata, D. / Sandy, P. / Hatton, C. / Romero, F.A. / Chiang, E. / Reimer, T. / Crawford, T. / Pardo, E. / Watson, V.G. / Tsui, V. / Cochran, A.G. / Zawadzke, L. / Harmange, J.C. / Audia, J.E. / Bryant, B.M. / Cummings, R.T. / Magnuson, S.R. / Grogan, J.L. / Bellon, S.F. / Albrecht, B.K. / Sims, R.J. / Lora, J.M.
History
DepositionAug 21, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 20, 2016Provider: repository / Type: Initial release
Revision 1.1Jun 29, 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 / citation / database_2 / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _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
C: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,8716
Polymers41,9763
Non-polymers8953
Water6,395355
1
A: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,2902
Polymers13,9921
Non-polymers2981
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,2902
Polymers13,9921
Non-polymers2981
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,2902
Polymers13,9921
Non-polymers2981
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)110.588, 34.034, 117.727
Angle α, β, γ (deg.)90.000, 103.930, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein CREB-binding protein


Mass: 13992.011 Da / Num. of mol.: 3 / 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, histone acetyltransferase
#2: Chemical ChemComp-58N / (4R)-6-(1-tert-butyl-1H-pyrazol-4-yl)-4-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one


Mass: 298.383 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C17H22N4O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 355 / 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: 2.56 Å3/Da / Density % sol: 51.98 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 9
Details: 0.1 M BICINE:NaOH pH 9.0, 20% (w/v) PEG 6000 (CPI703)

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.9786 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 20, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 1.85→50 Å / Num. obs: 36503 / % possible obs: 99.7 % / Redundancy: 3.6 % / Rmerge(I) obs: 0.094 / Rpim(I) all: 0.058 / Rrim(I) all: 0.111 / Χ2: 1.064 / Net I/av σ(I): 13.508 / Net I/σ(I): 7.2 / Num. measured all: 132348
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.85-1.923.50.6835980.6740.4220.8031.0999
1.92-1.993.60.49136170.8410.3020.5781.08899.3
1.99-2.083.60.32535830.9060.1990.3821.09199.5
2.08-2.193.60.22836100.9490.1390.2681.06499.8
2.19-2.333.60.18136180.9650.1110.2131.08199.9
2.33-2.513.70.14236570.9780.0860.1671.03799.9
2.51-2.763.70.11436470.9870.0680.1331.04599.9
2.76-3.163.70.08636590.990.0520.11.07599.9
3.16-3.993.70.05336880.9960.0320.0621.06699.7
3.99-503.60.03838260.9970.0240.0451.00699.8

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMAC5.8.0069refinement
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3DWY

3dwy


Resolution: 1.86→50 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.937 / SU B: 6.232 / SU ML: 0.099 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.129 / ESU R Free: 0.129 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2202 1816 5 %RANDOM
Rwork0.1723 ---
obs0.1746 34687 99.41 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 74.68 Å2 / Biso mean: 24.308 Å2 / Biso min: 8.41 Å2
Baniso -1Baniso -2Baniso -3
1--0.19 Å2-0 Å2-1.3 Å2
2--0.54 Å20 Å2
3---0.26 Å2
Refinement stepCycle: final / Resolution: 1.86→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2901 0 66 357 3324
Biso mean--20.01 28.95 -
Num. residues----345
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0210.023066
X-RAY DIFFRACTIONr_bond_other_d0.0020.022900
X-RAY DIFFRACTIONr_angle_refined_deg1.9872.0064174
X-RAY DIFFRACTIONr_angle_other_deg0.9633.0076689
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9475344
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.66124.61154
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.08615535
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.2731519
X-RAY DIFFRACTIONr_chiral_restr0.1060.2431
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0213407
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02705
X-RAY DIFFRACTIONr_mcbond_it1.0991.1091382
X-RAY DIFFRACTIONr_mcbond_other1.0821.1061381
X-RAY DIFFRACTIONr_mcangle_it1.6881.6461724
LS refinement shellResolution: 1.855→1.904 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.287 101 -
Rwork0.259 2487 -
all-2588 -
obs--95.71 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.5965-0.2206-0.21360.7195-0.14890.88270.06790.12520.0542-0.0247-0.0483-0.00770.01350.0126-0.01970.0790.0146-0.00540.01530.00780.072414.198266.549345.4911
23.4492-0.70910.96631.8259-0.38191.6278-0.1151-0.1624-0.19620.2190.19260.0219-0.09840.0537-0.07760.08950.0285-0.01580.10630.00070.036833.816759.8999.711
33.8597-1.00560.49710.9513-0.1611.04680.16460.40730.1808-0.1266-0.1876-0.05810.01540.09510.0230.07620.0479-0.00860.07740.03670.06650.264160.99130.0872
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1083 - 1196
2X-RAY DIFFRACTION2B1084 - 1196
3X-RAY DIFFRACTION3C1080 - 1197

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