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- PDB-7evj: Crystal structure of CBP bromodomain liganded with 9c -

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Basic information

Entry
Database: PDB / ID: 7evj
TitleCrystal structure of CBP bromodomain liganded with 9c
ComponentsCREB-binding protein
KeywordsPROTEIN BINDING / Histone acetyltransferase / CBP / Bromodomain
Function / homology
Function and homology information


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 / 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 / regulation of smoothened signaling pathway ...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 / 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 / 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 / NFE2L2 regulating anti-oxidant/detoxification enzymes / embryonic digit morphogenesis / protein-lysine-acetyltransferase activity / protein acetylation / 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 / stimulatory C-type lectin receptor signaling pathway / Zygotic genome activation (ZGA) / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / histone acetyltransferase complex / canonical NF-kappaB signal transduction / Attenuation phase / histone acetyltransferase activity / cellular response to nutrient levels / histone acetyltransferase / positive regulation of double-strand break repair via homologous recombination / regulation of cellular response to heat / : / NPAS4 regulates expression of target genes / Regulation of lipid metabolism by PPARalpha / 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 / Transcriptional activation of mitochondrial biogenesis / Formation of the beta-catenin:TCF transactivating complex / PPARA activates gene expression / Cytoprotection by HMOX1 / protein destabilization / chromatin DNA binding / Evasion by RSV of host interferon responses / Transcriptional regulation of white adipocyte differentiation / NOTCH1 Intracellular Domain Regulates Transcription / positive regulation of protein localization to nucleus / Pre-NOTCH Transcription and Translation / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / tau protein binding / transcription coactivator binding / Activation of anterior HOX genes in hindbrain development during early embryogenesis / cellular response to UV / p53 binding / : / rhythmic process / transcription corepressor activity / 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 / damaged DNA binding / RNA polymerase II-specific DNA-binding transcription factor binding / transcription coactivator activity / response to hypoxia / nuclear body / chromatin binding / regulation of DNA-templated transcription / chromatin / positive regulation of DNA-templated transcription / SARS-CoV-2 activates/modulates innate and adaptive immune responses / negative regulation of transcription by RNA polymerase II / signal transduction / positive regulation of transcription by RNA polymerase II / 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-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, conserved site / Bromodomain signature. / Bromodomain / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
Chem-JE9 / PHOSPHATE ION / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.57 Å
AuthorsXiang, Q. / Wang, C. / Wu, T. / Zhang, Y. / Zhang, C. / Luo, G. / Wu, X. / Shen, H. / Xu, Y.
CitationJournal: J.Med.Chem. / Year: 2022
Title: Design, Synthesis, and Biological Evaluation of 1-(Indolizin-3-yl)ethan-1-ones as CBP Bromodomain Inhibitors for the Treatment of Prostate Cancer.
Authors: Xiang, Q. / Wang, C. / Wu, T. / Zhang, C. / Hu, Q. / Luo, G. / Hu, J. / Zhuang, X. / Zou, L. / Shen, H. / Wu, X. / Zhang, Y. / Kong, X. / Liu, J. / Xu, Y.
History
DepositionMay 21, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 16, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)16,5984
Polymers15,8911
Non-polymers7073
Water59433
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area130 Å2
ΔGint-4 kcal/mol
Surface area7330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)79.450, 79.450, 45.110
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number90
Space group name H-MP4212

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Components

#1: Protein CREB-binding protein


Mass: 15891.296 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 1081-1197
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-JE9 / 3-acetyl-1-((3-(1-cyclopropyl-1H-pyrazol-4-yl)-2-fluoro-5-(hydroxymethyl)phenyl)carbamoyl)indolizin-7-yl dimethylcarbamate


Mass: 519.524 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H26FN5O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: PO4
#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.: 33 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.24 Å3/Da / Density % sol: 45.08 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 4.6 / Details: 0.2 M NH4H2PO4, 20% PEG 3350, pH 4.6, and 20% Gly

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97852 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 23, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97852 Å / Relative weight: 1
ReflectionResolution: 2.57→79.45 Å / Num. obs: 4962 / % possible obs: 100 % / Redundancy: 11.9 % / CC1/2: 0.998 / Rmerge(I) obs: 0.107 / Rpim(I) all: 0.032 / Rrim(I) all: 0.112 / Net I/σ(I): 18.3 / Num. measured all: 59161 / Scaling rejects: 53
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.57-2.6812.20.54272115930.9380.1610.5665.3100
8.9-79.459.20.03914311550.9980.0140.04133.799.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0189refinement
Aimless0.5.32data scaling
PDB_EXTRACT3.27data extraction
iMOSFLMdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5XXH

5xxh


Resolution: 2.57→56.18 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.937 / SU B: 7.093 / SU ML: 0.157 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.662 / ESU R Free: 0.257 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2093 272 5.5 %RANDOM
Rwork0.1869 ---
obs0.1882 4674 99.94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 314.22 Å2 / Biso mean: 41.498 Å2 / Biso min: 19.25 Å2
Baniso -1Baniso -2Baniso -3
1--0.95 Å20 Å20 Å2
2---0.95 Å2-0 Å2
3---1.89 Å2
Refinement stepCycle: final / Resolution: 2.57→56.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms944 0 49 35 1028
Biso mean--44.21 47.41 -
Num. residues----111
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.021022
X-RAY DIFFRACTIONr_bond_other_d0.0040.02929
X-RAY DIFFRACTIONr_angle_refined_deg1.8642.031390
X-RAY DIFFRACTIONr_angle_other_deg1.133.0062163
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.1185110
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.38524.31451
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.87915175
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.625157
X-RAY DIFFRACTIONr_chiral_restr0.0910.2138
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0211095
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02209
LS refinement shellResolution: 2.57→2.637 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.304 18 -
Rwork0.211 333 -
all-351 -
obs--100 %

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