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- PDB-5tb6: Structure of bromodomain of CREBBP with a pyrazolo[4,3-c]pyridin ... -

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Basic information

Entry
Database: PDB / ID: 5tb6
TitleStructure of bromodomain of CREBBP with a pyrazolo[4,3-c]pyridin fragment
ComponentsCREB-binding protein
KeywordsTRANSFERASE / Fragment / complex / bromodomain / Structural Genomics / Structural Genomics Consortium / SGC / trasnferase
Function / homology
Function and homology information


protein N-acetyltransferase activity / peptide lactyltransferase (CoA-dependent) activity / NFE2L2 regulating ER-stress associated genes / Activation of the TFAP2 (AP-2) family of transcription factors / NFE2L2 regulating inflammation associated genes / N-terminal peptidyl-lysine acetylation / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / NFE2L2 regulates pentose phosphate pathway genes / regulation of smoothened signaling pathway / NFE2L2 regulating MDR associated enzymes ...protein N-acetyltransferase activity / peptide lactyltransferase (CoA-dependent) activity / NFE2L2 regulating ER-stress associated genes / Activation of the TFAP2 (AP-2) family of transcription factors / NFE2L2 regulating inflammation associated genes / N-terminal peptidyl-lysine acetylation / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / NFE2L2 regulates pentose phosphate pathway genes / regulation of smoothened signaling pathway / 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 / Regulation of FOXO transcriptional activity by acetylation / RUNX3 regulates NOTCH signaling / NOTCH4 Intracellular Domain Regulates Transcription / Nuclear events mediated by NFE2L2 / 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 / embryonic digit morphogenesis / NFE2L2 regulating anti-oxidant/detoxification enzymes / histone H2AK5 acetyltransferase activity / histone H2AK9 acetyltransferase activity / histone H2BK5 acetyltransferase activity / histone H2BK12 acetyltransferase activity / histone H3K36 acetyltransferase activity / histone H3K4 acetyltransferase activity / protein-lysine-acetyltransferase activity / histone H3K56 acetyltransferase activity / histone H3K23 acetyltransferase activity / histone H4K12 acetyltransferase activity / protein acetylation / histone H4K16 acetyltransferase activity / histone H3K14 acetyltransferase activity / histone H3K9 acetyltransferase activity / histone H4K5 acetyltransferase activity / histone H4K8 acetyltransferase activity / histone H3K122 acetyltransferase activity / homeostatic process / Notch-HLH transcription pathway / Formation of paraxial mesoderm / positive regulation of transforming growth factor beta receptor signaling pathway / acetyltransferase activity / FOXO-mediated transcription of cell death genes / histone H3K18 acetyltransferase activity / histone H3K27 acetyltransferase activity / stimulatory C-type lectin receptor signaling pathway / Zygotic genome activation (ZGA) / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / histone acetyltransferase activity / histone acetyltransferase complex / canonical NF-kappaB signal transduction / Attenuation phase / positive regulation of double-strand break repair via homologous recombination / cellular response to nutrient levels / histone acetyltransferase / regulation of cellular response to heat / : / 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) / Heme signaling / Formation of the beta-catenin:TCF transactivating complex / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / transcription coactivator binding / protein destabilization / Cytoprotection by HMOX1 / Evasion by RSV of host interferon responses / Transcriptional regulation of white adipocyte differentiation / chromatin DNA binding / NOTCH1 Intracellular Domain Regulates Transcription / Pre-NOTCH Transcription and Translation / tau protein binding / positive regulation of protein localization to nucleus / 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 / cellular response to UV / transcription corepressor activity / 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 / transcription regulator complex / DNA-binding transcription factor binding / 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 / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily / Zinc finger, RING/FYVE/PHD-type / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-77X / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.79 Å
AuthorsFilippakopoulos, P. / Picaud, S. / Knapp, S. / von Delft, F. / Bountra, C. / Arrowsmith, C.H. / Edwards, A. / Structural Genomics Consortium (SGC)
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Wellcome Trust095751/Z/11/Z United Kingdom
Wellcome Trust092809/Z/10/Z United Kingdom
CitationJournal: ACS Med Chem Lett / Year: 2016
Title: Discovery of New Bromodomain Scaffolds by Biosensor Fragment Screening.
Authors: Navratilova, I. / Aristotelous, T. / Picaud, S. / Chaikuad, A. / Knapp, S. / Filappakopoulos, P. / Hopkins, A.L.
History
DepositionSep 11, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Oct 12, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 11, 2017Group: Database references
Revision 1.2Jan 17, 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)14,5413
Polymers14,2231
Non-polymers3172
Water2,828157
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area120 Å2
ΔGint1 kcal/mol
Surface area7660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)24.450, 45.340, 104.630
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: 14223.349 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CREBBP, CBP / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q92793, histone acetyltransferase
#2: Chemical ChemComp-77X / 1-(3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)propan-1-one


Mass: 255.315 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H17N3O
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 157 / 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: 2.04 Å3/Da / Density % sol: 39.67 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 0.15M KSCN 15% PEG 3350 5% EtGly

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.52 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: May 24, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.52 Å / Relative weight: 1
ReflectionResolution: 1.79→21.52 Å / Num. all: 11330 / Num. obs: 11330 / % possible obs: 97.8 % / Redundancy: 3.3 % / Rpim(I) all: 0.062 / Rrim(I) all: 0.118 / Rsym value: 0.1 / Net I/av σ(I): 5.77 / Net I/σ(I): 8.3 / Num. measured all: 37484
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
1.79-1.893.10.5391.4197.7
1.89-23.50.3882198.2
2-2.143.40.2493197.7
2.14-2.313.30.1744.3196.3
2.31-2.533.20.1375.6196.8
2.53-2.833.10.0997.6197.5
2.83-3.273.20.0789.1198.2
3.27-43.60.05212.9199.8
4-5.663.60.04513.2199.8
5.66-21.523.30.0484.4197.6

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 56.19 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.5 Å21.52 Å
Translation3.5 Å21.52 Å

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Processing

Software
NameVersionClassification
SCALA3.3.16data scaling
PHASER2.1.4phasing
REFMAC5.5.0110refinement
PDB_EXTRACT3.2data extraction
MOSFLMdata processing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3DWY

3dwy


Resolution: 1.79→21.52 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.92 / SU B: 5.153 / SU ML: 0.091 / SU R Cruickshank DPI: 0.1399 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.14 / ESU R Free: 0.148
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2435 543 4.8 %RANDOM
Rwork0.1716 ---
obs0.1749 10748 97.39 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å
Displacement parametersBiso max: 66.9 Å2 / Biso mean: 13.875 Å2 / Biso min: 5.6 Å2
Baniso -1Baniso -2Baniso -3
1--0.19 Å20 Å20 Å2
2--0.44 Å20 Å2
3----0.25 Å2
Refinement stepCycle: final / Resolution: 1.79→21.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms997 0 23 157 1177
Biso mean--20.65 24.07 -
Num. residues----119
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0221057
X-RAY DIFFRACTIONr_bond_other_d0.0010.02761
X-RAY DIFFRACTIONr_angle_refined_deg1.4782.0031432
X-RAY DIFFRACTIONr_angle_other_deg0.9353.0021829
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1425120
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.49924.03852
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.42215189
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.98158
X-RAY DIFFRACTIONr_chiral_restr0.0820.2146
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0211144
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02211
X-RAY DIFFRACTIONr_mcbond_it3.0213605
X-RAY DIFFRACTIONr_mcbond_other0.9973231
X-RAY DIFFRACTIONr_mcangle_it4.3465989
X-RAY DIFFRACTIONr_scbond_it6.8338452
X-RAY DIFFRACTIONr_scangle_it8.84911442
LS refinement shellResolution: 1.79→1.836 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.42 38 -
Rwork0.326 759 -
all-797 -
obs--96.14 %
Refinement TLS params.Method: refined / Origin x: 6.0841 Å / Origin y: 20.537 Å / Origin z: 15.3215 Å
111213212223313233
T0.0732 Å2-0.0011 Å20.0045 Å2-0.0574 Å20.0062 Å2--0.0663 Å2
L0.2214 °20.1374 °2-0.0621 °2-0.2747 °2-0.3615 °2--0.6282 °2
S0.0021 Å °0.0442 Å °-0.0023 Å °0.0094 Å °-0.0116 Å °-0.0056 Å °0.0097 Å °-0.0002 Å °0.0096 Å °

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