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- PDB-5w0e: CREBBP bromodomain in complex with Cpd19 (3-(7-(difluoromethyl)-6... -

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Entry
Database: PDB / ID: 5w0e
TitleCREBBP bromodomain in complex with Cpd19 (3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide)
ComponentsCREB-binding protein
KeywordsTRANSCRIPTION REGULATOR/INHIBITOR / CREBBP / Bromodomain / small molecule inhibitor / TRANSCRIPTION REGULATOR-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-9U4 / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.41 Å
AuthorsMurray, J.M.
CitationJournal: J. Med. Chem. / Year: 2017
Title: A Unique Approach to Design Potent and Selective Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP) Inhibitors.
Authors: Bronner, S.M. / Murray, J. / Romero, F.A. / Lai, K.W. / Tsui, V. / Cyr, P. / Beresini, M.H. / de Leon Boenig, G. / Chen, Z. / Choo, E.F. / Clark, K.R. / Crawford, T.D. / Jayaram, H. / ...Authors: Bronner, S.M. / Murray, J. / Romero, F.A. / Lai, K.W. / Tsui, V. / Cyr, P. / Beresini, M.H. / de Leon Boenig, G. / Chen, Z. / Choo, E.F. / Clark, K.R. / Crawford, T.D. / Jayaram, H. / Kaufman, S. / Li, R. / Li, Y. / Liao, J. / Liang, X. / Liu, W. / Ly, J. / Maher, J. / Wai, J. / Wang, F. / Zheng, A. / Zhu, X. / Magnuson, S.
History
DepositionMay 30, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 21, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 4, 2023Group: 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

Downloads & links

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Assembly

Deposited unit
A: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,1562
Polymers17,6301
Non-polymers5261
Water2,396133
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)33.815, 49.386, 79.819
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: 17629.973 Da / Num. of mol.: 1 / 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-9U4 / 3-[7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl]-N-methyl-1-(oxan-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide


Mass: 525.593 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H33F2N7O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 133 / 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: 1.89 Å3/Da / Density % sol: 34.93 % / Mosaicity: 1.696 ° / Mosaicity esd: 0.008 °
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 6.5 / Details: 0.2M MgCl2, 0.1M Bis-Tris pH6.5, 22% PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17B1 / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Sep 25, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.4→26.339 Å / Num. obs: 34991 / % possible obs: 90.4 % / Redundancy: 3.5 % / Biso Wilson estimate: 16.62 Å2 / Rmerge(I) obs: 0.117 / Rpim(I) all: 0.07 / Rrim(I) all: 0.138 / Χ2: 1.443 / Net I/σ(I): 5.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.57-1.633.50.5750.7650.3480.6771.09994
1.63-1.693.40.4590.8680.2740.5381.14894.3
1.69-1.773.40.3410.9150.2070.4011.30294.1
1.77-1.863.40.2660.9380.1620.3131.49692.7
1.86-1.983.50.2020.9570.1240.2381.52192.2
1.98-2.133.50.1580.9730.0960.1861.60990.2
2.13-2.353.50.130.9770.0790.1531.49290.4
2.35-2.683.60.1060.9830.0630.1241.43689
2.68-3.383.70.0960.9810.0580.1131.52688.2
3.38-503.70.0870.9850.0510.1011.79379.5

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
DENZOdata collection
SCALEPACKdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACT3.22data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5I8B

5i8b


Resolution: 1.41→26.339 Å / SU ML: 0.17 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 25.18
RfactorNum. reflection% reflection
Rfree0.2599 1298 5.07 %
Rwork0.2285 --
obs0.2301 25617 96.71 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 63.2 Å2 / Biso mean: 21.7129 Å2 / Biso min: 11.54 Å2
Refinement stepCycle: final / Resolution: 1.41→26.339 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms962 0 38 133 1133
Biso mean--18.85 30.73 -
Num. residues----114
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061054
X-RAY DIFFRACTIONf_angle_d0.8521438
X-RAY DIFFRACTIONf_chiral_restr0.075145
X-RAY DIFFRACTIONf_plane_restr0.006208
X-RAY DIFFRACTIONf_dihedral_angle_d16.368433
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 9

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.4101-1.46660.32471420.29312563270593
1.4666-1.53330.31111570.2672657281497
1.5333-1.61420.27571480.25162673282198
1.6142-1.71530.29481370.2362711284898
1.7153-1.84770.25581440.22762724286898
1.8477-2.03360.23941460.22132708285497
2.0336-2.32770.26871400.21582746288698
2.3277-2.9320.23161270.23162776290398
2.932-26.34310.25971570.22142761291893
Refinement TLS params.Method: refined / Origin x: -11.6969 Å / Origin y: 2.993 Å / Origin z: -6.2217 Å
111213212223313233
T0.1079 Å2-0.0059 Å20.0151 Å2-0.1194 Å2-0.0141 Å2--0.1357 Å2
L1.3986 °20.0496 °20.4937 °2-1.5748 °20.2196 °2--2.0659 °2
S0.0201 Å °0.0768 Å °-0.1116 Å °-0.0241 Å °0.0411 Å °-0.016 Å °0.0882 Å °-0.0234 Å °-0.0003 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1083 - 1196
2X-RAY DIFFRACTION1allM1 - 133
3X-RAY DIFFRACTION1allB1

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