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- PDB-5w0f: CREBBP Bromodomain in complex with Cpd3 ((S)-1-(3-(6-(1-methyl-1H... -

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Basic information

Entry
Database: PDB / ID: 5w0f
TitleCREBBP Bromodomain in complex with Cpd3 ((S)-1-(3-(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
KeywordsTRANSCRIPTION REGULATOR/INHIBITOR / CREBBP / Bromodomain / small molecule inhibitor / TRANSFERASE-INHIBITOR complex / TRANSCRIPTION REGULATOR-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-9U7 / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.6 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)18,0772
Polymers17,6301
Non-polymers4471
Water2,090116
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)35.195, 48.256, 80.502
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-9U7 / 1-{3-[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: 446.545 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H30N6O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 116 / 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: 36.56 % / Mosaicity: 0.734 °
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 6.5 / Details: 0.2 M Li2SO4, 0.1M Bis-Tris pH 6.5, 19% 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: Dec 15, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.6→30.91 Å / Num. obs: 18355 / % possible obs: 97.4 % / Redundancy: 6.8 % / Biso Wilson estimate: 20.18 Å2 / Rmerge(I) obs: 0.101 / Rpim(I) all: 0.042 / Rrim(I) all: 0.109 / Χ2: 1.436 / Net I/σ(I): 9.3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.6-1.666.40.680.880.2830.7381.07694.4
1.66-1.726.90.5380.9320.2190.5821.108100
1.72-1.87.10.380.960.1520.411.171100
1.8-1.97.10.2680.980.1080.2891.29100
1.9-2.027.10.180.9880.0730.1941.36399.9
2.02-2.177.10.1240.9940.050.1341.44499.9
2.17-2.3970.0990.9930.040.1071.45799.7
2.39-2.746.90.0870.9940.0360.0941.68799.4
2.74-3.456.60.0950.990.040.1042.24796.4
3.45-5060.0630.9940.0280.0691.53585.5

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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: 1.6→30.91 Å / SU ML: 0.15 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 19.72
RfactorNum. reflection% reflection
Rfree0.206 966 5.28 %
Rwork0.1849 --
obs0.1862 18302 97.74 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 80.26 Å2 / Biso mean: 25.1247 Å2 / Biso min: 13.7 Å2
Refinement stepCycle: final / Resolution: 1.6→30.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms962 0 33 116 1111
Biso mean--18.28 32.21 -
Num. residues----114
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061071
X-RAY DIFFRACTIONf_angle_d0.8671463
X-RAY DIFFRACTIONf_chiral_restr0.051146
X-RAY DIFFRACTIONf_plane_restr0.006191
X-RAY DIFFRACTIONf_dihedral_angle_d13.995641
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 7

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.6004-1.68480.26831330.23812443257699
1.6848-1.79030.23861430.211824892632100
1.7903-1.92850.19431380.182625042642100
1.9285-2.12250.22281520.165224762628100
2.1225-2.42960.1861490.163425122661100
2.4296-3.06060.22331410.18832531267299
3.0606-30.91560.1881100.18792381249188
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)
11.308-0.09720.82571.0642-0.23512.25080.0591-0.0578-0.0940.06230.009-0.01840.12140.0464-00.14180.00260.00560.1470.00060.158712.58482.83936.9614
20.0669-0.0307-0.0210.0350.01080.03480.08320.05640.0241-0.2398-0.12890.2690.0209-0.1927-0.00090.15970.0128-0.00630.2097-0.01330.19441.13723.2039-2.1613
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain A and resseq 1083:1196)A1083 - 1196
2X-RAY DIFFRACTION2(chain A and resseq 1201:1201)A1201

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