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- PDB-8fvf: Bromodomain of EP300 liganded with CCS-1477 -

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Basic information

Entry
Database: PDB / ID: 8fvf
TitleBromodomain of EP300 liganded with CCS-1477
ComponentsHistone acetyltransferase p300
KeywordsTRANSCRIPTION/INHIBITOR / bromodomain / small molecule ligand / complex / TRANSCRIPTION / TRANSCRIPTION-INHIBITOR complex
Function / homology
Function and homology information


behavioral defense response / peptidyl-lysine propionylation / histone lactyltransferase (CoA-dependent) activity / peptidyl-lysine crotonylation / peptidyl-lysine butyrylation / histone butyryltransferase activity / histone H3K122 acetyltransferase activity / swimming / peptide butyryltransferase activity / histone H2B acetyltransferase activity ...behavioral defense response / peptidyl-lysine propionylation / histone lactyltransferase (CoA-dependent) activity / peptidyl-lysine crotonylation / peptidyl-lysine butyrylation / histone butyryltransferase activity / histone H3K122 acetyltransferase activity / swimming / peptide butyryltransferase activity / histone H2B acetyltransferase activity / thigmotaxis / peptide 2-hydroxyisobutyryltransferase activity / histone crotonyltransferase activity / protein propionyltransferase activity / NOTCH2 intracellular domain regulates transcription / peptidyl-lysine acetylation / lysine N-acetyltransferase activity, acting on acetyl phosphate as donor / cellular response to L-leucine / histone H4 acetyltransferase activity / internal peptidyl-lysine acetylation / histone H3 acetyltransferase 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 / acetylation-dependent protein binding / NGF-stimulated transcription / STAT3 nuclear events downstream of ALK signaling / Polo-like kinase mediated events / 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 / regulation of androgen receptor signaling pathway / positive regulation by host of viral transcription / regulation of mitochondrion organization / Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells / RUNX3 regulates NOTCH signaling / face morphogenesis / Regulation of FOXO transcriptional activity by acetylation / NOTCH4 Intracellular Domain Regulates Transcription / Regulation of gene expression by Hypoxia-inducible Factor / regulation of glycolytic process / Nuclear events mediated by NFE2L2 / Regulation of NFE2L2 gene expression / NOTCH3 Intracellular Domain Regulates Transcription / platelet formation / NFE2L2 regulating anti-oxidant/detoxification enzymes / TRAF6 mediated IRF7 activation / megakaryocyte development / NFE2L2 regulating tumorigenic genes / peptide-lysine-N-acetyltransferase activity / FOXO-mediated transcription of cell death genes / macrophage derived foam cell differentiation / nuclear androgen receptor binding / regulation of tubulin deacetylation / STAT family protein binding / internal protein amino acid acetylation / acyltransferase activity / protein acetylation / positive regulation of transforming growth factor beta receptor signaling pathway / fat cell differentiation / Formation of paraxial mesoderm / RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known / PI5P Regulates TP53 Acetylation / Zygotic genome activation (ZGA) / stimulatory C-type lectin receptor signaling pathway / cellular response to nutrient levels / RUNX3 regulates p14-ARF / acetyltransferase activity / NF-kappaB binding / histone acetyltransferase complex / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / Attenuation phase / canonical NF-kappaB signal transduction / negative regulation of protein-containing complex assembly / negative regulation of gluconeogenesis / somitogenesis / positive regulation of T-helper 17 cell lineage commitment / pre-mRNA intronic binding / regulation of cellular response to heat / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / histone acetyltransferase activity / skeletal muscle tissue development / histone acetyltransferase / transcription initiation-coupled chromatin remodeling / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / Regulation of TP53 Activity through Acetylation / positive regulation of TORC1 signaling / RORA activates gene expression / CD209 (DC-SIGN) signaling / negative regulation of autophagy / B cell differentiation / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / SUMOylation of transcription cofactors / regulation of signal transduction by p53 class mediator / regulation of autophagy
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 / NICKEL (II) ION / Histone acetyltransferase p300
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsSchonbrunn, E. / Bikowitz, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2024
Title: Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition.
Authors: Shendy, N.A.M. / Bikowitz, M. / Sigua, L.H. / Zhang, Y. / Mercier, A. / Khashana, Y. / Nance, S. / Liu, Q. / Delahunty, I.M. / Robinson, S. / Goel, V. / Rees, M.G. / Ronan, M.A. / Wang, T. / ...Authors: Shendy, N.A.M. / Bikowitz, M. / Sigua, L.H. / Zhang, Y. / Mercier, A. / Khashana, Y. / Nance, S. / Liu, Q. / Delahunty, I.M. / Robinson, S. / Goel, V. / Rees, M.G. / Ronan, M.A. / Wang, T. / Kocak, M. / Roth, J.A. / Wang, Y. / Freeman, B.B. / Orr, B.A. / Abraham, B.J. / Roussel, M.F. / Schonbrunn, E. / Qi, J. / Durbin, A.D.
History
DepositionJan 18, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 7, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 5, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Histone acetyltransferase p300
B: Histone acetyltransferase p300
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,09717
Polymers27,2172
Non-polymers1,88015
Water3,945219
1
A: Histone acetyltransferase p300
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,5579
Polymers13,6091
Non-polymers9498
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Histone acetyltransferase p300
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,5398
Polymers13,6091
Non-polymers9317
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)103.150, 103.150, 59.220
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number90
Space group name H-MP4212

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Histone acetyltransferase p300 / p300 HAT / E1A-associated protein p300 / Histone butyryltransferase p300 / Histone ...p300 HAT / E1A-associated protein p300 / Histone butyryltransferase p300 / Histone crotonyltransferase p300 / Protein 2-hydroxyisobutyryltransferase p300 / Protein lactyltransferas p300 / Protein propionyltransferase p300


Mass: 13608.522 Da / Num. of mol.: 2 / Fragment: bromodomain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EP300, P300 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): RIL
References: UniProt: Q09472, histone acetyltransferase, Transferases; Acyltransferases; Transferring groups other than aminoacyl groups

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Non-polymers , 5 types, 234 molecules

#2: 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
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical
ChemComp-NI / NICKEL (II) ION


Mass: 58.693 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: Ni
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 219 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.89 Å3/Da / Density % sol: 57.5 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.1M Sodium chloride, 0.1M HEPES pH7.5, 1.6M Ammonium sulfate

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jun 20, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→19.74 Å / Num. obs: 19185 / % possible obs: 99.8 % / Redundancy: 13.4 % / Biso Wilson estimate: 28.2 Å2 / CC1/2: 0.998 / Rrim(I) all: 0.175 / Net I/σ(I): 16
Reflection shellResolution: 2.1→2.2 Å / Redundancy: 13.7 % / Mean I/σ(I) obs: 3.5 / Num. unique obs: 2449 / CC1/2: 0.891 / Rrim(I) all: 0.88 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.20.1-4487refinement
XDSJan 31, 2020data reduction
XSCALEdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→19.74 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 21.96 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2389 1056 5.5 %
Rwork0.1813 --
obs0.1844 19184 99.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.1→19.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1888 0 104 219 2211
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.008
X-RAY DIFFRACTIONf_angle_d1.157
X-RAY DIFFRACTIONf_dihedral_angle_d6.511266
X-RAY DIFFRACTIONf_chiral_restr0.07285
X-RAY DIFFRACTIONf_plane_restr0.007353
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.20.25111300.19842224X-RAY DIFFRACTION100
2.2-2.310.25251290.18642214X-RAY DIFFRACTION100
2.31-2.460.26151290.19072225X-RAY DIFFRACTION100
2.46-2.640.28671300.20162235X-RAY DIFFRACTION100
2.64-2.910.28031310.19672248X-RAY DIFFRACTION100
2.91-3.330.27281320.19112259X-RAY DIFFRACTION100
3.33-4.190.19641330.16142300X-RAY DIFFRACTION100
4.19-19.740.20591420.16912423X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 0.9162 Å / Origin y: 25.2641 Å / Origin z: 17.3696 Å
111213212223313233
T0.1592 Å2-0.0006 Å20.0117 Å2-0.0933 Å2-0.0054 Å2--0.126 Å2
L0.0245 °20.0523 °2-0.0034 °2-0.1881 °20.1311 °2--0.0677 °2
S-0.0158 Å °0.0219 Å °0.004 Å °0.0075 Å °0.0199 Å °0.015 Å °-0.0018 Å °-0.0056 Å °-0.0002 Å °
Refinement TLS groupSelection details: all

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