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- PDB-6v8k: Crystal structure of the p300 acetyltransferase domain with pepti... -

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Basic information

Entry
Database: PDB / ID: 6v8k
TitleCrystal structure of the p300 acetyltransferase domain with peptide-competitive inhibitor 2
ComponentsHistone acetyltransferase p300
KeywordsTRANSFERASE/INHIBITOR / epigenetics / chromatin / writer / TRANSFERASE / TRANSFERASE-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
COENZYME A / Chem-QS4 / Histone acetyltransferase p300
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.84 Å
AuthorsGardberg, A.S.
CitationJournal: Chemmedchem / Year: 2020
Title: Early Drug-Discovery Efforts towards the Identification of EP300/CBP Histone Acetyltransferase (HAT) Inhibitors.
Authors: Huhn, A.J. / Gardberg, A.S. / Poy, F. / Brucelle, F. / Vivat, V. / Cantone, N. / Patel, G. / Patel, C. / Cummings, R. / Sims, R. / Levell, J. / Audia, J.E. / Bommi-Reddy, A. / Wilson, J.E.
History
DepositionDec 11, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 1, 2020Provider: repository / Type: Initial release
Revision 1.1Jun 17, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Histone acetyltransferase p300
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,3024
Polymers37,1851
Non-polymers1,1163
Water1,65792
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)60.669, 60.669, 100.647
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number78
Space group name H-MP43

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Components

#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 propionyltransferase p300


Mass: 37185.480 Da / Num. of mol.: 1 / Mutation: Y1467F
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EP300, P300 / Production host: Escherichia coli (E. coli)
References: UniProt: Q09472, histone acetyltransferase, Transferases; Acyltransferases; Transferring groups other than aminoacyl groups
#2: Chemical ChemComp-COA / COENZYME A


Mass: 767.534 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H36N7O16P3S
#3: Chemical ChemComp-QS4 / 1-(2-methyl-1H-indol-3-yl)-2-[(2R)-2-methylpiperidin-1-yl]ethan-1-one


Mass: 270.369 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H22N2O / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 92 / 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: 2.49 Å3/Da / Density % sol: 50.61 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 0.24 mM HAT, 0.12 mM CoA, 0.75 mM ligand. 200+150 (+20) nL sitting drops. Internal focus screen with microseeding. 17.5% MPD, 0.1 M Tris pH 8, 2.5 % PEG3350. Cryo 30% MPD, 5% PEG 3350, 1 mM ligand

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.12723 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Feb 10, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.12723 Å / Relative weight: 1
ReflectionResolution: 1.84→100.65 Å / Num. obs: 26347 / % possible obs: 83.2 % / Redundancy: 6.5 % / CC1/2: 0.997 / Rmerge(I) obs: 0.038 / Rpim(I) all: 0.018 / Rrim(I) all: 0.047 / Net I/σ(I): 21.9 / Num. measured all: 172283
Reflection shellResolution: 1.84→1.94 Å / Redundancy: 5.8 % / Rmerge(I) obs: 0.441 / Mean I/σ(I) obs: 1.8 / Num. measured all: 12431 / Num. unique obs: 2150 / CC1/2: 0.931 / Rpim(I) all: 0.204 / Rrim(I) all: 0.522 / Net I/σ(I) obs: 1.8 / % possible all: 46.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimless0.5.31data scaling
PHASERphasing
REFMAC5.8.0158refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal

Resolution: 1.84→60.67 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.956 / SU B: 3.573 / SU ML: 0.103 / SU R Cruickshank DPI: 0.1549 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.155 / ESU R Free: 0.139
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2134 1292 4.9 %RANDOM
Rwork0.1786 ---
obs0.1804 25019 83.17 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 95.01 Å2 / Biso mean: 45.88 Å2 / Biso min: 24.57 Å2
Baniso -1Baniso -2Baniso -3
1-1.43 Å2-0 Å20 Å2
2--1.43 Å20 Å2
3----2.87 Å2
Refinement stepCycle: final / Resolution: 1.84→60.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2534 0 72 92 2698
Biso mean--44.58 44.09 -
Num. residues----315
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0192688
X-RAY DIFFRACTIONr_bond_other_d0.0020.022463
X-RAY DIFFRACTIONr_angle_refined_deg1.51.9783648
X-RAY DIFFRACTIONr_angle_other_deg0.932.9875703
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1075315
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.47322.727121
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.07615439
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.9111520
X-RAY DIFFRACTIONr_chiral_restr0.0890.2387
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212920
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02583
LS refinement shellResolution: 1.84→1.886 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.297 61 -
Rwork0.33 1269 -
obs--58.03 %

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