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- PDB-8gzc: Crystal structure of EP300 HAT domain in complex with compound 10 -

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Basic information

Entry
Database: PDB / ID: 8gzc
TitleCrystal structure of EP300 HAT domain in complex with compound 10
ComponentsHistone acetyltransferase p300
KeywordsTRANSFERASE / epigenetics / SBDD / Histone acetyltransferase
Function / homology
Function and homology information


behavioral defense response / negative regulation of protein oligomerization / peptidyl-lysine propionylation / histone lactyltransferase (CoA-dependent) activity / peptidyl-lysine crotonylation / peptidyl-lysine butyrylation / histone butyryltransferase activity / swimming / peptide butyryltransferase activity / regulation of tubulin deacetylation ...behavioral defense response / negative regulation of protein oligomerization / peptidyl-lysine propionylation / histone lactyltransferase (CoA-dependent) activity / peptidyl-lysine crotonylation / peptidyl-lysine butyrylation / histone butyryltransferase activity / swimming / peptide butyryltransferase activity / regulation of tubulin deacetylation / histone H2B acetyltransferase activity / internal protein amino acid acetylation / peptide 2-hydroxyisobutyryltransferase activity / histone crotonyltransferase activity / protein propionyltransferase activity / NOTCH2 intracellular domain regulates transcription / thigmotaxis / L-lysine N-acetyltransferase activity, acting on acetyl phosphate as donor / positive regulation of TORC2 signaling / internal peptidyl-lysine acetylation / histone H4 acetyltransferase activity / cellular response to L-leucine / histone H3 acetyltransferase activity / NFE2L2 regulating ER-stress associated genes / acetylation-dependent protein binding / Activation of the TFAP2 (AP-2) family of transcription factors / NFE2L2 regulating inflammation associated genes / NGF-stimulated transcription / N-terminal peptidyl-lysine acetylation / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / NFE2L2 regulates pentose phosphate pathway genes / STAT3 nuclear events downstream of ALK signaling / Polo-like kinase mediated events / NFE2L2 regulating MDR associated enzymes / host-mediated activation of viral transcription / TGFBR3 expression / regulation of androgen receptor signaling pathway / regulation of mitochondrion organization / 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 / face morphogenesis / platelet formation / NOTCH3 Intracellular Domain Regulates Transcription / regulation of glycolytic process / TRAF6 mediated IRF7 activation / NFE2L2 regulating tumorigenic genes / NFE2L2 regulating anti-oxidant/detoxification enzymes / megakaryocyte development / protein-lysine-acetyltransferase activity / nuclear androgen receptor binding / acyltransferase activity / STAT family protein binding / protein acetylation / histone H3K122 acetyltransferase activity / Formation of paraxial mesoderm / positive regulation of transforming growth factor beta receptor signaling pathway / acetyltransferase activity / FOXO-mediated transcription of cell death genes / histone H3K18 acetyltransferase activity / PI5P Regulates TP53 Acetylation / histone H3K27 acetyltransferase activity / stimulatory C-type lectin receptor signaling pathway / RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known / fat cell differentiation / Zygotic genome activation (ZGA) / histone acetyltransferase activity / histone acetyltransferase complex / RUNX3 regulates p14-ARF / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / canonical NF-kappaB signal transduction / NF-kappaB binding / negative regulation of gluconeogenesis / pre-mRNA intronic binding / Attenuation phase / negative regulation of protein-containing complex assembly / somitogenesis / positive regulation of T-helper 17 cell lineage commitment / cellular response to nutrient levels / skeletal muscle tissue development / histone acetyltransferase / regulation of cellular response to heat / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / positive regulation of DNA-binding transcription factor activity / Regulation of TP53 Activity through Acetylation / : / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / positive regulation of TORC1 signaling / Transcriptional and post-translational regulation of MITF-M expression and activity / CD209 (DC-SIGN) signaling / negative regulation of autophagy / B cell differentiation / transcription initiation-coupled chromatin remodeling / SUMOylation of transcription cofactors / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest
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-KQO / Histone acetyltransferase p300
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsTakahashi, M. / Hanzawa, H.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery of DS-9300: A Highly Potent, Selective, and Once-Daily Oral EP300/CBP Histone Acetyltransferase Inhibitor.
Authors: Kanada, R. / Kagoshima, Y. / Suzuki, T. / Nakamura, A. / Funami, H. / Watanabe, J. / Asano, M. / Takahashi, M. / Ubukata, O. / Suzuki, K. / Aikawa, T. / Sato, K. / Goto, M. / Setsu, G. / ...Authors: Kanada, R. / Kagoshima, Y. / Suzuki, T. / Nakamura, A. / Funami, H. / Watanabe, J. / Asano, M. / Takahashi, M. / Ubukata, O. / Suzuki, K. / Aikawa, T. / Sato, K. / Goto, M. / Setsu, G. / Ito, K. / Kihara, K. / Kuroha, M. / Kohno, T. / Ogiwara, H. / Isoyama, T. / Tominaga, Y. / Higuchi, S. / Naito, H.
History
DepositionSep 26, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 11, 2023Provider: repository / Type: Initial release
Revision 1.1Jan 25, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Nov 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: Histone acetyltransferase p300
B: Histone acetyltransferase p300
hetero molecules


Theoretical massNumber of molelcules
Total (without water)106,13510
Polymers104,8112
Non-polymers1,3238
Water5,062281
1
A: Histone acetyltransferase p300
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,0675
Polymers52,4061
Non-polymers6624
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Histone acetyltransferase p300
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,0675
Polymers52,4061
Non-polymers6624
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)43.500, 89.350, 91.600
Angle α, β, γ (deg.)116.600, 95.180, 91.780
Int Tables number1
Space group name H-MP1

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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 lactyltransferas p300 / Protein propionyltransferase p300


Mass: 52405.727 Da / Num. of mol.: 2 / Mutation: Y1467E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EP300, P300 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q09472, histone acetyltransferase
#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-KQO / (2~{R},4~{R})-4-fluoranyl-1-[1-(4-methoxyphenyl)cyclohexyl]carbonyl-~{N}-(1~{H}-pyrazolo[4,3-b]pyridin-5-yl)pyrrolidine-2-carboxamide


Mass: 465.520 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H28FN5O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 281 / 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: 3.02 Å3/Da / Density % sol: 59.21 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 15% PEG3350, 0.1 M HEPES

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: BL-1A / Wavelength: 1.1 Å
DetectorType: DECTRIS EIGER X 4M / Detector: PIXEL / Date: Feb 22, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 1.99→19.91 Å / Num. obs: 82690 / % possible obs: 96.8 % / Redundancy: 2.604 % / Biso Wilson estimate: 46.69 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.096 / Rrim(I) all: 0.118 / Χ2: 1.133 / Net I/σ(I): 5.74 / Num. measured all: 424926 / Scaling rejects: 673
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.99-2.041.5361.7450.291559612420101510.1672.46881.7
2.04-2.11.6271.3350.411865312200114640.2391.88894
2.1-2.161.6291.0470.521805211774110820.3141.48194.1
2.16-2.221.9081.1310.72097711514109930.371.47595.5
2.22-2.33.0491.0391.123376711144110760.2551.26199.4
2.3-2.383.0651.081.253259210682106350.511.3199.6
2.38-2.473.0290.6831.763120810382103020.6620.8399.2
2.47-2.573.0190.4852.433032510114100440.7950.58999.3
2.57-2.683.0060.3563.2428258946494000.8750.43399.3
2.68-2.812.9630.2714.1626835914090570.9140.33199.1
2.81-2.972.8770.1815.9425060876287100.9570.22399.4
2.97-3.152.6680.1347.5721815825881760.970.16799
3.15-3.362.8120.1039.9921615775276880.980.12799.2
3.36-3.632.8510.08512.3420390723471530.9860.10598.9
3.63-3.982.7020.06714.7417559660464980.990.08398.4
3.98-4.453.0190.05518.2117734595058750.9940.06698.7
4.45-5.143.0330.04619.4315849528052250.9950.05699
5.14-6.293.0260.04519.6813452451844450.9950.05498.4
6.29-8.92.9910.03720.7910102343833780.9970.04498.3
8.9-19.912.8120.03221.45087189818090.9970.03995.3

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHENIX1.19.1_4122refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7VI0

7vi0


Resolution: 2→19.91 Å / SU ML: 0.35 / Cross valid method: THROUGHOUT / σ(F): 1.91 / Phase error: 28.95 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2268 4086 5 %
Rwork0.1945 77702 -
obs0.1961 81788 98.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 175.89 Å2 / Biso mean: 65.3943 Å2 / Biso min: 30.61 Å2
Refinement stepCycle: final / Resolution: 2→19.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6925 0 74 281 7280
Biso mean--52.13 57.25 -
Num. residues----880
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 29

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2-2.020.43021510.42712558270996
2.02-2.050.40081340.40092604273896
2.05-2.070.38031330.37362647278096
2.07-2.10.3541350.36082537267296
2.1-2.130.35381310.35912640277196
2.13-2.160.38111310.35492609274096
2.16-2.190.37951280.33262660278897
2.19-2.230.30241380.31112641277998
2.23-2.260.34471370.307327102847100
2.26-2.30.3791230.293827322855100
2.3-2.340.3111390.270627002839100
2.34-2.390.27281360.25327452881100
2.39-2.440.29131540.244626852839100
2.44-2.490.31671360.241826802816100
2.49-2.550.26281480.224527192867100
2.55-2.610.27541480.218426782826100
2.61-2.680.24771470.217227152862100
2.68-2.760.25391410.217327102851100
2.76-2.850.31211320.227127282860100
2.85-2.950.23631670.207526972864100
2.95-3.070.24131340.19327132847100
3.07-3.210.22931340.200826982832100
3.21-3.380.20531490.188227252874100
3.38-3.590.19421380.182327012839100
3.59-3.860.20281400.163927002840100
3.86-4.250.20051580.151126942852100
4.25-4.850.16711510.137427102861100
4.86-6.090.17751520.161426792831100
6.09-19.910.19261410.15272687282899
Refinement TLS params.Method: refined / Origin x: -21.6866 Å / Origin y: 7.5607 Å / Origin z: -2.5766 Å
111213212223313233
T0.3006 Å2-0.0338 Å2-0.0317 Å2-0.4092 Å2-0.0201 Å2--0.3218 Å2
L0.6377 °20.0031 °2-0.0697 °2-0.8124 °2-0.4679 °2--0.606 °2
S-0.0407 Å °0.046 Å °-0.0167 Å °-0.1119 Å °0.1155 Å °-0.0176 Å °0.0744 Å °-0.1869 Å °-0.0768 Å °
Refinement TLS groupSelection details: all

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