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- PDB-6ay5: CREBBP bromodomain in complex with Cpd17 (5-(7-(difluoromethyl)-6... -

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Basic information

Entry
Database: PDB / ID: 6ay5
TitleCREBBP bromodomain in complex with Cpd17 (5-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-3-methylbenzo[d]thiazol-2(3H)-one)
ComponentsCREB-binding protein
KeywordsTRANSFERASE/TRANSFERASE inhibitor / CREBBP / Bromodomain / SBDD / TRANSFERASE-TRANSFERASE inhibitor complex
Function / homology
Function and homology information


peptide lactyltransferase (CoA-dependent) activity / regulation of smoothened signaling pathway / 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 / histone H3K18 acetyltransferase activity / N-terminal peptidyl-lysine acetylation / histone H3K27 acetyltransferase activity / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production ...peptide lactyltransferase (CoA-dependent) activity / regulation of smoothened signaling pathway / 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 / histone H3K18 acetyltransferase activity / N-terminal peptidyl-lysine acetylation / histone H3K27 acetyltransferase activity / 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 / Regulation of gene expression by Hypoxia-inducible Factor / Nuclear events mediated by NFE2L2 / NOTCH4 Intracellular Domain Regulates Transcription / FOXO-mediated transcription of cell death genes / Regulation of NFE2L2 gene expression / negative regulation of transcription by RNA polymerase I / NOTCH3 Intracellular Domain Regulates Transcription / TRAF6 mediated IRF7 activation / NFE2L2 regulating anti-oxidant/detoxification enzymes / peptide-lysine-N-acetyltransferase activity / NFE2L2 regulating tumorigenic genes / embryonic digit morphogenesis / homeostatic process / protein acetylation / Notch-HLH transcription pathway / positive regulation of transforming growth factor beta receptor signaling pathway / Formation of paraxial mesoderm / stimulatory C-type lectin receptor signaling pathway / acetyltransferase activity / Zygotic genome activation (ZGA) / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / histone acetyltransferase complex / positive regulation of double-strand break repair via homologous recombination / Attenuation phase / cellular response to nutrient levels / Transcriptional and post-translational regulation of MITF-M expression and activity / canonical NF-kappaB signal transduction / histone acetyltransferase activity / regulation of cellular response to heat / histone acetyltransferase / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / RORA activates gene expression / Regulation of lipid metabolism by PPARalpha / NPAS4 regulates expression of target genes / CD209 (DC-SIGN) signaling / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / protein destabilization / Formation of the beta-catenin:TCF transactivating complex / Heme signaling / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / chromatin DNA binding / Evasion by RSV of host interferon responses / NOTCH1 Intracellular Domain Regulates Transcription / transcription coactivator binding / Pre-NOTCH Transcription and Translation / Transcriptional regulation of white adipocyte differentiation / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / positive regulation of protein localization to nucleus / Activation of anterior HOX genes in hindbrain development during early embryogenesis / transcription corepressor activity / cellular response to UV / rhythmic process / p53 binding / Circadian Clock / TRAF3-dependent IRF activation pathway / HATs acetylate histones / protein-containing complex assembly / DNA-binding transcription factor binding / RNA polymerase II-specific DNA-binding transcription factor binding / Estrogen-dependent gene expression / transcription regulator complex / damaged DNA binding / transcription coactivator activity / nuclear body / response to hypoxia / chromatin binding / regulation of DNA-templated transcription / chromatin / 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. / 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-C3V / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.44 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
DepositionSep 7, 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)14,5086
Polymers13,7191
Non-polymers7895
Water2,810156
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)34.435, 49.232, 80.965
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein CREB-binding protein


Mass: 13718.702 Da / Num. of mol.: 1 / Fragment: Bromodomain (UNP residue 1083-1197)
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

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Non-polymers , 5 types, 161 molecules

#2: Chemical ChemComp-C3V / 5-[7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl]-3-methyl-1,3-benzothiazol-2(3H)-one


Mass: 426.482 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H20F2N4OS
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#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: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 156 / 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: 2.5 Å3/Da / Density % sol: 50.83 % / Mosaicity: 0.686 °
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: BL17U1 / Wavelength: 0.9793 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Mar 23, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 1.44→50 Å / Num. obs: 25692 / % possible obs: 99.5 % / Redundancy: 6.9 % / Biso Wilson estimate: 19.78 Å2 / Rmerge(I) obs: 0.081 / Rpim(I) all: 0.033 / Rrim(I) all: 0.085 / Χ2: 1.264 / Net I/σ(I): 9.8 / Num. measured all: 178474
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allΧ2% possible allRrim(I) all
1.44-1.496.90.97825190.7650.3951.15100
1.49-1.5570.64325130.880.2591.22199.40.694
1.55-1.6270.4725140.9230.191.24699.50.507
1.62-1.716.90.3325580.9720.1341.28599.80.357
1.71-1.8170.21725420.9830.0871.32499.80.234
1.81-1.9570.14225420.9920.0571.3771000.153
1.95-2.1570.1126020.9920.0451.6131000.119
2.15-2.4670.09225840.9930.0371.5891000.099
2.46-3.16.90.06126150.9960.0250.99199.80.066
3.1-506.80.06327030.9940.0260.84397.30.069

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
PHENIXdev_2747refinement
PDB_EXTRACT3.22data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdbid 5I8B

5i8b


Resolution: 1.44→26.229 Å / SU ML: 0.16 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 19.99
RfactorNum. reflection% reflection
Rfree0.1838 1311 5.11 %
Rwork0.1632 --
obs0.1644 25638 98.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 67.13 Å2 / Biso mean: 25.0328 Å2 / Biso min: 14.27 Å2
Refinement stepCycle: final / Resolution: 1.44→26.229 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms966 0 50 156 1172
Biso mean--24.71 34.53 -
Num. residues----115
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0131110
X-RAY DIFFRACTIONf_angle_d1.3351521
X-RAY DIFFRACTIONf_chiral_restr0.089147
X-RAY DIFFRACTIONf_plane_restr0.01199
X-RAY DIFFRACTIONf_dihedral_angle_d20.578418
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 (%)
1.4346-1.4920.35511330.24972529266294
1.492-1.55990.22791190.203926842803100
1.5599-1.64210.21261450.16972672281799
1.6421-1.7450.1871480.154726952843100
1.745-1.87970.19131550.150127022857100
1.8797-2.06880.19071600.14327032863100
2.0688-2.3680.17991530.148527282881100
2.368-2.98280.18211570.172427632920100
2.9828-26.23380.16861410.16282851299298
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)
10.90520.20480.34870.815-0.05261.90490.025-0.0607-0.03460.0710.0144-0.03860.11880.0372-0.01020.14170.01880.0010.13850.01240.157412.4013.0466.982
25.5446-1.6165-3.64411.25231.8024.29060.11850.12990.1415-0.12770.04830.1311-0.1975-0.4173-0.01250.2419-0.0052-0.01350.23480.02030.24111.2783.189-1.762
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 1083:1197 )A1083 - 1197
2X-RAY DIFFRACTION2( CHAIN A AND RESID 1201:1201 )A1201

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