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- PDB-8fup: Bromodomain of CBP liganded with BMS-536924 and CCS-1477 -

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Basic information

Entry
Database: PDB / ID: 8fup
TitleBromodomain of CBP liganded with BMS-536924 and CCS-1477
ComponentsCREB-binding protein
KeywordsTRANSCRIPTION/INHIBITOR / bromodomain / small molecule ligand / complex / TRANSCRIPTION-INHIBITOR complex
Function / homology
Function and homology information


peptide lactyltransferase (CoA-dependent) activity / 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 ...peptide lactyltransferase (CoA-dependent) activity / 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 / Regulation of FOXO transcriptional activity by acetylation / NOTCH4 Intracellular Domain Regulates Transcription / 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 / NFE2L2 regulating tumorigenic genes / peptide-lysine-N-acetyltransferase activity / FOXO-mediated transcription of cell death 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 / non-canonical NF-kappaB signal transduction / Zygotic genome activation (ZGA) / stimulatory C-type lectin receptor signaling pathway / cellular response to nutrient levels / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / acetyltransferase activity / positive regulation of double-strand break repair via homologous recombination / 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 / Heme signaling / protein destabilization / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Evasion by RSV of host interferon responses / Cytoprotection by HMOX1 / NOTCH1 Intracellular Domain Regulates Transcription / chromatin DNA binding / Pre-NOTCH Transcription and Translation / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / transcription coactivator binding / 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 / RNA polymerase II-specific DNA-binding transcription factor binding / 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 / cytoplasm / cytosol
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, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
Chem-JHL / Chem-N6I / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsSchonbrunn, E. / Bikowitz, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: Structural basis of CBP and EP300 interaction with kinase inhibitors
Authors: Schonbrunn, E. / Bikowitz, M.
History
DepositionJan 18, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 7, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: CREB-binding protein
B: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,4939
Polymers27,6962
Non-polymers1,7977
Water5,477304
1
A: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,9875
Polymers13,8481
Non-polymers1,1394
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,5074
Polymers13,8481
Non-polymers6593
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.950, 53.460, 110.310
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein CREB-binding protein / Histone lysine acetyltransferase CREBBP / Protein-lysine acetyltransferase CREBBP


Mass: 13847.882 Da / Num. of mol.: 2 / Fragment: bromodomain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CREBBP, CBP / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): RIL
References: UniProt: Q92793, histone acetyltransferase, Transferases; Acyltransferases; Transferring groups other than aminoacyl groups
#2: Chemical ChemComp-N6I / (3M)-4-{[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}-3-[4-methyl-6-(morpholin-4-yl)-1H-benzimidazol-2-yl]pyridin-2(1H)-one


Mass: 479.959 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H26ClN5O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-JHL / (6S)-1-[3,4-bis(fluoranyl)phenyl]-6-[5-(3,5-dimethyl-1,2-oxazol-4-yl)-1-(4-methoxycyclohexyl)benzimidazol-2-yl]piperidin-2-one / CCS1477 / Inobrodib


Mass: 534.597 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H32F2N4O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 304 / 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: 2.29 Å3/Da / Density % sol: 46.2 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop
Details: 0.2 M Ammonium sulfate, 30% w/v Polyethylene glycol 8000
PH range: 7.5

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.03319 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jul 15, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03319 Å / Relative weight: 1
ReflectionResolution: 1.7→48.11 Å / Num. obs: 28656 / % possible obs: 99.7 % / Redundancy: 5.4 % / Biso Wilson estimate: 17.6 Å2 / CC1/2: 0.927 / Rrim(I) all: 0.42 / Net I/σ(I): 9.2
Reflection shellResolution: 1.7→1.74 Å / Redundancy: 6.4 % / Mean I/σ(I) obs: 2.2 / Num. unique obs: 2100 / CC1/2: 0.757 / Rrim(I) all: 1.04 / % possible all: 99.1

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Processing

Software
NameVersionClassification
PHENIX1.20.1-4487refinement
XDSJan 10, 2022data reduction
XSCALEJan 10, 2022data scaling
PHENIX1.20.1-4487phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→48.11 Å / SU ML: 0.22 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 20.52 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2125 1432 5 %
Rwork0.186 --
obs0.1873 28652 99.68 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.7→48.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1902 0 128 304 2334
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.012
X-RAY DIFFRACTIONf_angle_d1.164
X-RAY DIFFRACTIONf_dihedral_angle_d16.063279
X-RAY DIFFRACTIONf_chiral_restr0.063288
X-RAY DIFFRACTIONf_plane_restr0.008359
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7-1.760.35611410.32052677X-RAY DIFFRACTION99
1.76-1.830.26531390.24042649X-RAY DIFFRACTION99
1.83-1.910.21971420.20772686X-RAY DIFFRACTION99
1.91-2.020.23141400.19512674X-RAY DIFFRACTION100
2.02-2.140.23711430.20482711X-RAY DIFFRACTION100
2.14-2.310.21591410.18342677X-RAY DIFFRACTION100
2.31-2.540.22351450.18352750X-RAY DIFFRACTION100
2.54-2.910.2111430.18372718X-RAY DIFFRACTION100
2.91-3.660.19371450.17052766X-RAY DIFFRACTION100
3.66-48.110.17631530.1612912X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 2.3907 Å / Origin y: -8.2749 Å / Origin z: 15.027 Å
111213212223313233
T0.1023 Å20.0129 Å20.0245 Å2-0.1064 Å20.0079 Å2--0.1522 Å2
L0.176 °2-0.0329 °20.3193 °2-0.2332 °2-0.055 °2--1.2382 °2
S-0.0188 Å °0.017 Å °0.0128 Å °0.0587 Å °-0.0078 Å °0.022 Å °0.0237 Å °0.0685 Å °0.035 Å °
Refinement TLS groupSelection details: all

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