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- PDB-5cgp: Selective pharmacological inhibition of the CREB binding protein ... -

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Basic information

Entry
Database: PDB / ID: 5cgp
TitleSelective pharmacological inhibition of the CREB binding protein bromodomain regulates inflammatory cytokines in macrophages and RGS4 in neurons
ComponentsCREB-binding protein
KeywordsTRANSCRIPTION/INHIBITOR / inhibitor / complex / TRANSCRIPTION-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-53W / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.96 Å
AuthorsChekler, E.L. / Jones, L.H.
CitationJournal: Chem.Biol. / Year: 2015
Title: Transcriptional Profiling of a Selective CREB Binding Protein Bromodomain Inhibitor Highlights Therapeutic Opportunities.
Authors: Chekler, E.L. / Pellegrino, J.A. / Lanz, T.A. / Denny, R.A. / Flick, A.C. / Coe, J. / Langille, J. / Basak, A. / Liu, S. / Stock, I.A. / Sahasrabudhe, P. / Bonin, P.D. / Lee, K. / Pletcher, M.T. / Jones, L.H.
History
DepositionJul 9, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 20, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)14,6842
Polymers14,2231
Non-polymers4611
Water1,06359
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)90.090, 33.740, 40.010
Angle α, β, γ (deg.)90.00, 92.70, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein CREB-binding protein /


Mass: 14223.349 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-53W / 5-(3,5-dimethyl-1,2-oxazol-4-yl)-2-[2-(4-methoxyphenyl)ethyl]-1-[2-(morpholin-4-yl)ethyl]-1H-benzimidazole


Mass: 460.568 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H32N4O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 59 / 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: 2.14 Å3/Da / Density % sol: 42.4 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 15-20% PEG 8000, 0.2M CaAcetate, 0.1 M cacodylate ph 6-7

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.54178 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Sep 5, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.9→31.595 Å / Num. obs: 9495 / % possible obs: 98.2 % / Redundancy: 5.6 % / Biso Wilson estimate: 17.8 Å2 / Rmerge(I) obs: 0.141 / Net I/σ(I): 10.8
Reflection shellResolution: 1.9→1.912 Å / Redundancy: 2 % / Rmerge(I) obs: 0.675 / Mean I/σ(I) obs: 1.2 / % possible all: 76.5

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
XDSdata reduction
SCALAdata scaling
BUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3P1F

3p1f


Resolution: 1.96→31.59 Å / Cor.coef. Fo:Fc: 0.8951 / Cor.coef. Fo:Fc free: 0.8645 / SU R Cruickshank DPI: 0.202 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.202 / SU Rfree Blow DPI: 0.17 / SU Rfree Cruickshank DPI: 0.17
RfactorNum. reflection% reflectionSelection details
Rfree0.2493 865 9.94 %RANDOM
Rwork0.2092 ---
obs0.213 8701 98.55 %-
Displacement parametersBiso mean: 17.15 Å2
Baniso -1Baniso -2Baniso -3
1-1.6173 Å20 Å2-1.3164 Å2
2---2.4752 Å20 Å2
3---0.858 Å2
Refine analyzeLuzzati coordinate error obs: 0.283 Å
Refinement stepCycle: LAST / Resolution: 1.96→31.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms960 0 34 59 1053
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.011057HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.071466HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d360SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes29HARMONIC2
X-RAY DIFFRACTIONt_gen_planes175HARMONIC5
X-RAY DIFFRACTIONt_it1057HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.85
X-RAY DIFFRACTIONt_other_torsion18.75
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion121SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1247SEMIHARMONIC4
LS refinement shellResolution: 1.96→2.19 Å / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.2564 243 10.23 %
Rwork0.2102 2132 -
all0.2147 2375 -
obs--98.55 %
Refinement TLS params.Method: refined / Origin x: -13.1916 Å / Origin y: 2.4761 Å / Origin z: 7.5506 Å
111213212223313233
T-0.0908 Å20.014 Å20.0184 Å2--0.1134 Å20.0186 Å2---0.0538 Å2
L1.0166 °20.408 °20.1297 °2-1.6587 °20.0519 °2--2.5246 °2
S0.0258 Å °0.0402 Å °0.027 Å °0.101 Å °0.0776 Å °-0.0268 Å °-0.0935 Å °0.0575 Å °-0.1034 Å °
Refinement TLS groupSelection details: { A|* }

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