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- PDB-5ktx: CREBBP bromodomain in complex with Cpd59 ((S)-1-(3-((2-fluoro-4-(... -

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Basic information

Entry
Database: PDB / ID: 5ktx
TitleCREBBP bromodomain in complex with Cpd59 ((S)-1-(3-((2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)ethanone)
ComponentsCREB-binding protein
KeywordsTRANSFERASE / CREBBP bromodomain
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-6XH / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.27 Å
AuthorsMurray, J.M. / Noland, C.
CitationJournal: J. Med. Chem. / Year: 2016
Title: Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300.
Authors: Crawford, T.D. / Romero, F.A. / Lai, K.W. / Tsui, V. / Taylor, A.M. / de Leon Boenig, G. / Noland, C.L. / Murray, J. / Ly, J. / Choo, E.F. / Hunsaker, T.L. / Chan, E.W. / Merchant, M. / ...Authors: Crawford, T.D. / Romero, F.A. / Lai, K.W. / Tsui, V. / Taylor, A.M. / de Leon Boenig, G. / Noland, C.L. / Murray, J. / Ly, J. / Choo, E.F. / Hunsaker, T.L. / Chan, E.W. / Merchant, M. / Kharbanda, S. / Gascoigne, K.E. / Kaufman, S. / Beresini, M.H. / Liao, J. / Liu, W. / Chen, K.X. / Chen, Z. / Conery, A.R. / Cote, A. / Jayaram, H. / Jiang, Y. / Kiefer, J.R. / Kleinheinz, T. / Li, Y. / Maher, J. / Pardo, E. / Poy, F. / Spillane, K.L. / Wang, F. / Wang, J. / Wei, X. / Xu, Z. / Xu, Z. / Yen, I. / Zawadzke, L. / Zhu, X. / Bellon, S. / Cummings, R. / Cochran, A.G. / Albrecht, B.K. / Magnuson, S.
History
DepositionJul 12, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 2, 2016Provider: repository / Type: Initial release
Revision 1.1Dec 21, 2016Group: Database references
Revision 1.2Mar 6, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,1725
Polymers13,5451
Non-polymers6274
Water4,125229
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)35.255, 49.320, 80.253
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein CREB-binding protein


Mass: 13545.468 Da / Num. of mol.: 1 / Fragment: bromodomain (UNP residues 1085-1196)
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-6XH / 1-[3-[[2-fluoranyl-4-(1-methylpyrazol-4-yl)phenyl]amino]-1-[(3~{S})-oxolan-3-yl]-6,7-dihydro-4~{H}-pyrazolo[4,3-c]pyridin-5-yl]ethanone


Mass: 424.471 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H25FN6O2
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 229 / 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: 2.58 Å3/Da / Density % sol: 52.24 %
Crystal growTemperature: 287 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 0.2 M potassium thiocyanate, 0.1 M Bis-Tris pH 5.5, 5% v/v ethylene glycol, 23% PEG 3350

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Data collection

DiffractionMean temperature: 277 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Apr 16, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.27→24.66 Å / Num. obs: 36093 / % possible obs: 96 % / Redundancy: 6.4 % / Rsym value: 0.04 / Net I/av σ(I): 9.818 / Net I/σ(I): 25.9
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
1.27-1.33.80.2982.6170.8
1.3-1.344.20.253.1183.6
1.34-1.384.90.2363.3192.6
1.38-1.426.10.1814.3198.8
1.42-1.4770.1465.3199.9
1.47-1.527.10.1166.7199.9
1.52-1.587.10.0948.2199.9
1.58-1.647.10.089.6199.9
1.64-1.717.10.06811.2199.9
1.71-1.87.10.05812.8199.9
1.8-1.897.10.04914.8199.9
1.89-2.0170.04316.2199.9
2.01-2.1570.03917.61100
2.15-2.326.90.035191100
2.32-2.546.90.03220.6199.9
2.54-2.846.90.03219.2199.8
2.84-3.286.70.02920.6199.9
3.28-4.026.70.02818.1199.8
4.02-5.686.80.02618.4199.7
5.68-24.6660.0314.5198.1

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALA3.3.22data scaling
PHASERphasing
PHENIXdev-2363_2363refinement
PDB_EXTRACT3.2data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.27→24.66 Å / SU ML: 0.1 / Cross valid method: FREE R-VALUE / σ(F): 1.89 / Phase error: 15.86
RfactorNum. reflection% reflection
Rfree0.1721 1814 5.03 %
Rwork0.1656 --
obs0.1659 36066 95.65 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 52.65 Å2 / Biso mean: 15.7222 Å2 / Biso min: 5.66 Å2
Refinement stepCycle: final / Resolution: 1.27→24.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms954 0 44 229 1227
Biso mean--16.52 29.56 -
Num. residues----114
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0051035
X-RAY DIFFRACTIONf_angle_d0.8721407
X-RAY DIFFRACTIONf_chiral_restr0.072142
X-RAY DIFFRACTIONf_plane_restr0.006181
X-RAY DIFFRACTIONf_dihedral_angle_d19.808386
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 13

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.27-1.30430.2053880.20151897198569
1.3043-1.34270.23881370.18552204234183
1.3427-1.38610.18831340.18622518265293
1.3861-1.43560.16311440.16542720286499
1.4356-1.49310.17521290.159127122841100
1.4931-1.5610.15881370.151827162853100
1.561-1.64330.15781650.152227242889100
1.6433-1.74620.18311390.153727372876100
1.7462-1.8810.16881260.158927712897100
1.881-2.07020.16961460.159827652911100
2.0702-2.36960.17151550.152927662921100
2.3696-2.98460.19391530.174428052958100
2.9846-24.66460.15541610.17312917307899
Refinement TLS params.Method: refined / Origin x: 12.132 Å / Origin y: -2.9812 Å / Origin z: -6.6804 Å
111213212223313233
T0.0547 Å2-0.0055 Å2-0.0047 Å2-0.0436 Å2-0.0008 Å2--0.0629 Å2
L1.1134 °20.0665 °2-0.8148 °2-0.5959 °2-0.2941 °2--2.2752 °2
S0.0551 Å °0.0085 Å °0.0662 Å °-0.0012 Å °-0.0078 Å °0.0207 Å °-0.1403 Å °-0.0035 Å °-0.0406 Å °
Refinement TLS groupSelection details: chain 'A' and (resseq 1084:1194)

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