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- PDB-5w0i: CREBBP Bromodomain in complex with Cpd8 (1-(3-(7-(difluoromethyl)... -

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Entry
Database: PDB / ID: 5w0i
TitleCREBBP Bromodomain in complex with Cpd8 (1-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydrofuran-3-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one)
ComponentsCREB-binding protein
KeywordsTRANSFERASE/INHIBITOR / CREBBP / Bromodomain / small molecule inhibitor / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


Activation of the TFAP2 (AP-2) family of transcription factors / Regulation of FOXO transcriptional activity by acetylation / TRAF6 mediated IRF7 activation / Nuclear events mediated by NFE2L2 / Attenuation phase / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / RUNX1 regulates transcription of genes involved in differentiation of myeloid cells / Formation of the beta-catenin:TCF transactivating complex / NOTCH1 Intracellular Domain Regulates Transcription / RUNX3 regulates NOTCH signaling ...Activation of the TFAP2 (AP-2) family of transcription factors / Regulation of FOXO transcriptional activity by acetylation / TRAF6 mediated IRF7 activation / Nuclear events mediated by NFE2L2 / Attenuation phase / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / RUNX1 regulates transcription of genes involved in differentiation of myeloid cells / Formation of the beta-catenin:TCF transactivating complex / NOTCH1 Intracellular Domain Regulates Transcription / RUNX3 regulates NOTCH signaling / Regulation of gene expression by Hypoxia-inducible Factor / cAMP response element binding protein binding / Notch-HLH transcription pathway / Transcriptional and post-translational regulation of MITF-M expression and activity / positive regulation of cell adhesion molecule production / germ-line stem cell population maintenance / negative regulation of viral process / Regulation of lipid metabolism by PPARalpha / Cytoprotection by HMOX1 / Estrogen-dependent gene expression / CD209 (DC-SIGN) signaling / peptide lactyltransferase (CoA-dependent) activity / outer kinetochore / protein K48-linked deubiquitination / histone H3K18 acetyltransferase activity / N-terminal peptidyl-lysine acetylation / histone H3K27 acetyltransferase activity / negative regulation of interferon-beta production / MRF binding / peroxisome proliferator activated receptor binding / face morphogenesis / negative regulation of transcription by RNA polymerase I / cellular response to hepatocyte growth factor stimulus / acetyltransferase activity / histone acetyltransferase activity / positive regulation of transforming growth factor beta receptor signaling pathway / SMAD binding / positive regulation of dendritic spine development / TFIIB-class transcription factor binding / histone acetyltransferase complex / : / protein-lysine-acetyltransferase activity / positive regulation of G1/S transition of mitotic cell cycle / long-term memory / histone acetyltransferase / positive regulation of double-strand break repair via homologous recombination / energy homeostasis / canonical NF-kappaB signal transduction / behavioral response to cocaine / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / cellular response to nutrient levels / RNA polymerase II transcription regulatory region sequence-specific DNA binding / chromatin DNA binding / cellular response to virus / positive regulation of non-canonical NF-kappaB signal transduction / PML body / positive regulation of protein localization to nucleus / double-strand break repair via homologous recombination / protein destabilization / transcription coactivator binding / RNA polymerase II transcription regulator complex / disordered domain specific binding / p53 binding / cellular response to UV / transcription corepressor activity / rhythmic process / transcription regulator complex / DNA-binding transcription factor binding / molecular adaptor activity / damaged DNA binding / RNA polymerase II-specific DNA-binding transcription factor binding / transcription coactivator activity / protein stabilization / nuclear body / protein domain specific binding / chromatin binding / positive regulation of gene expression / regulation of transcription by RNA polymerase II / regulation of DNA-templated transcription / positive regulation of DNA-templated transcription / chromatin / protein-containing complex binding / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / protein-containing complex / DNA binding / zinc ion binding / nucleoplasm / nucleus / 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 / : / 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 finger, ZZ type / Zinc-binding domain, present in Dystrophin, CREB-binding protein. / 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-9UA / Histone lysine acetyltransferase CREBBP
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.43 Å
AuthorsMurray, J.M.
CitationJournal: J. Med. Chem. / Year: 2017
Title: GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP).
Authors: Romero, F.A. / Murray, J. / Lai, K.W. / Tsui, V. / Albrecht, B.K. / An, L. / Beresini, M.H. / de Leon Boenig, G. / Bronner, S.M. / Chan, E.W. / Chen, K.X. / Chen, Z. / Choo, E.F. / Clagg, K. ...Authors: Romero, F.A. / Murray, J. / Lai, K.W. / Tsui, V. / Albrecht, B.K. / An, L. / Beresini, M.H. / de Leon Boenig, G. / Bronner, S.M. / Chan, E.W. / Chen, K.X. / Chen, Z. / Choo, E.F. / Clagg, K. / Clark, K. / Crawford, T.D. / Cyr, P. / de Almeida Nagata, D. / Gascoigne, K.E. / Grogan, J.L. / Hatzivassiliou, G. / Huang, W. / Hunsaker, T.L. / Kaufman, S. / Koenig, S.G. / Li, R. / Li, Y. / Liang, X. / Liao, J. / Liu, W. / Ly, J. / Maher, J. / Masui, C. / Merchant, M. / Ran, Y. / Taylor, A.M. / Wai, J. / Wang, F. / Wei, X. / Yu, D. / Zhu, B.Y. / Zhu, X. / Magnuson, S.
History
DepositionMay 30, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 7, 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)18,3755
Polymers17,6301
Non-polymers7454
Water2,648147
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)34.879, 48.602, 80.763
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 1083-1198
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Crebbp, Cbp / Production host: Escherichia coli (E. coli) / References: UniProt: P45481, histone acetyltransferase
#2: Chemical ChemComp-9UA / 1-{3-[7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl]-1-[(3S)-oxolan-3-yl]-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl}ethan-1-one


Mass: 496.552 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H30F2N6O2
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


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


Mass: 18.015 Da / Num. of mol.: 147 / 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: 1.94 Å3/Da / Density % sol: 36.64 % / Mosaicity: 0.297 °
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 6.5 / Details: 0.2 M Li2SO4, 0.1M Bis-Tris pH 6.5, 23% PEG33500

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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: Jan 5, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.43→31.06 Å / Num. obs: 25858 / % possible obs: 98.8 % / Redundancy: 3.5 % / Biso Wilson estimate: 18.56 Å2 / Rmerge(I) obs: 0.094 / Rpim(I) all: 0.059 / Rrim(I) all: 0.112 / Χ2: 1.892 / Net I/σ(I): 10
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.43-1.483.40.530.7410.3280.6270.82698.5
1.48-1.543.50.3820.8380.2360.4520.8999.9
1.54-1.613.50.3030.9130.1850.3571.01399.9
1.61-1.73.60.2240.9480.1370.2641.07999.9
1.7-1.83.60.170.9690.1030.21.25899.9
1.8-1.943.60.1270.9780.0770.1491.56899.8
1.94-2.143.60.0990.9820.060.1161.918100
2.14-2.453.50.1020.9790.0620.123.21999.9
2.45-3.083.40.0970.970.0620.1164.16999.2
3.08-503.10.0720.9840.0470.0863.12491.7

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Phasing

PhasingMethod: molecular replacement

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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: 1.43→31.06 Å / SU ML: 0.13 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 19.19
RfactorNum. reflection% reflection
Rfree0.192 1325 5.13 %
Rwork0.1742 --
obs0.1752 25805 98.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 53.51 Å2 / Biso mean: 23.7792 Å2 / Biso min: 13.35 Å2
Refinement stepCycle: final / Resolution: 1.43→31.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms957 0 86 147 1190
Biso mean--25.22 33.65 -
Num. residues----114
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0141127
X-RAY DIFFRACTIONf_angle_d1.4791545
X-RAY DIFFRACTIONf_chiral_restr0.103147
X-RAY DIFFRACTIONf_plane_restr0.011199
X-RAY DIFFRACTIONf_dihedral_angle_d23.354417
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 (%)
1.4298-1.48710.27211400.23932654279499
1.4871-1.55470.25121220.208727192841100
1.5547-1.63670.19241420.182127232865100
1.6367-1.73920.22791610.170427272888100
1.7392-1.87350.16871510.161527102861100
1.8735-2.0620.18391600.162227102870100
2.062-2.36030.18521540.156327522906100
2.3603-2.97340.21091540.18892769292399
2.9734-31.0670.17651410.17062716285793
Refinement TLS params.Method: refined / Origin x: 11.3868 Å / Origin y: 2.9864 Å / Origin z: 6.2134 Å
111213212223313233
T0.123 Å20.0067 Å20.0177 Å2-0.1376 Å20.0132 Å2--0.1505 Å2
L1.4478 °2-0.0484 °21.1573 °2-1.2488 °2-0.1906 °2--2.7161 °2
S0.0732 Å °-0.0569 Å °-0.0612 Å °0.0259 Å °0.0158 Å °0.0359 Å °0.1076 Å °-0.029 Å °0.0002 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1084 - 1197
2X-RAY DIFFRACTION1allZ1
3X-RAY DIFFRACTION1allM1 - 147
4X-RAY DIFFRACTION1allS1 - 3

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