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- PDB-7vi0: Crystal structure of EP300 HAT domain in complex with compound 11 -

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Basic information

Entry
Database: PDB / ID: 7vi0
TitleCrystal structure of EP300 HAT domain in complex with compound 11
ComponentsHistone acetyltransferase p300
KeywordsTRANSFERASE / epigenetics / SBDD / Histone acetyltransferase
Function / homology
Function and homology information


behavioral defense response / peptidyl-lysine propionylation / peptidyl-lysine crotonylation / peptidyl-lysine butyrylation / histone butyryltransferase activity / swimming / peptide butyryltransferase activity / histone H2B acetyltransferase activity / thigmotaxis / internal protein amino acid acetylation ...behavioral defense response / peptidyl-lysine propionylation / peptidyl-lysine crotonylation / peptidyl-lysine butyrylation / histone butyryltransferase activity / swimming / peptide butyryltransferase activity / histone H2B acetyltransferase activity / thigmotaxis / internal protein amino acid acetylation / peptide 2-hydroxyisobutyryltransferase activity / histone crotonyltransferase activity / protein propionyltransferase activity / histone H4K16 propionyltransferase activity / NOTCH2 intracellular domain regulates transcription / peptidyl-lysine acetylation / positive regulation of TORC2 signaling / L-lysine N-acetyltransferase activity, acting on acetyl phosphate as donor / internal peptidyl-lysine acetylation / histone H4 acetyltransferase activity / cellular response to L-leucine / histone H3 acetyltransferase activity / NFE2L2 regulating ER-stress associated genes / protein 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 / histone lactyltransferase (CoA-dependent) activity / 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 / TGFBR3 expression / positive regulation by host of viral transcription / regulation of androgen receptor signaling pathway / regulation of mitochondrion organization / Regulation of FOXO transcriptional activity by acetylation / Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells / RUNX3 regulates NOTCH signaling / Nuclear events mediated by NFE2L2 / NOTCH4 Intracellular Domain Regulates Transcription / face morphogenesis / Regulation of NFE2L2 gene expression / Regulation of gene expression by Hypoxia-inducible Factor / regulation of glycolytic process / platelet formation / NOTCH3 Intracellular Domain Regulates Transcription / TRAF6 mediated IRF7 activation / NFE2L2 regulating tumorigenic genes / megakaryocyte development / NFE2L2 regulating anti-oxidant/detoxification enzymes / regulation of tubulin deacetylation / protein-lysine-acetyltransferase activity / STAT family protein binding / nuclear androgen receptor binding / acyltransferase activity / protein acetylation / histone acetyltransferase activity / positive regulation of transforming growth factor beta receptor signaling pathway / Formation of paraxial mesoderm / PI5P Regulates TP53 Acetylation / fat cell differentiation / acetyltransferase activity / FOXO-mediated transcription of cell death genes / RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known / stimulatory C-type lectin receptor signaling pathway / Zygotic genome activation (ZGA) / RUNX3 regulates p14-ARF / histone acetyltransferase complex / 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 / negative regulation of protein-containing complex assembly / cellular response to nutrient levels / somitogenesis / pre-mRNA intronic binding / Attenuation phase / positive regulation of T-helper 17 cell lineage commitment / histone H4K16 acetyltransferase activity / histone H3K56 acetyltransferase activity / histone H3K23 acetyltransferase activity / histone H2AK5 acetyltransferase activity / histone H2AK9 acetyltransferase activity / histone H2BK5 acetyltransferase activity / histone H2BK12 acetyltransferase activity / histone H3K4 acetyltransferase activity / histone H3K27 acetyltransferase activity / histone H3K36 acetyltransferase activity / histone H3K122 acetyltransferase activity / regulation of cellular response to heat / histone H3K18 acetyltransferase activity / histone H3K9 acetyltransferase activity / histone H3K14 acetyltransferase activity / histone H4K5 acetyltransferase activity / histone H4K8 acetyltransferase activity / histone H4K12 acetyltransferase activity
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-6YI / Histone acetyltransferase p300
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsTakahashi, M. / Hanzawa, H.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2022
Title: Discovery of EP300/CBP histone acetyltransferase inhibitors through scaffold hopping of 1,4-oxazepane ring.
Authors: Kanada, R. / Kagoshima, Y. / Asano, M. / Suzuki, T. / Murata, T. / Haruta, M. / Takahashi, M. / Ubukata, O. / Hashimoto, K. / Obata, K. / Kihara, K. / Kuroha, M. / Banjo, T. / Togashi, N. / ...Authors: Kanada, R. / Kagoshima, Y. / Asano, M. / Suzuki, T. / Murata, T. / Haruta, M. / Takahashi, M. / Ubukata, O. / Hashimoto, K. / Obata, K. / Kihara, K. / Kuroha, M. / Banjo, T. / Togashi, N. / Sato, K. / Yamamoto, Y. / Suzuki, K. / Isoyama, T. / Tominaga, Y. / Higuchi, S. / Naito, H.
History
DepositionSep 24, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 27, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)106,16910
Polymers104,8112
Non-polymers1,3588
Water9,134507
1
A: Histone acetyltransferase p300
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,0855
Polymers52,4061
Non-polymers6794
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Histone acetyltransferase p300
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,0855
Polymers52,4061
Non-polymers6794
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)43.555, 88.361, 90.655
Angle α, β, γ (deg.)116.520, 94.380, 91.360
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 1162 through 1172 or (resid 1173...
21(chain B and (resid 1162 through 1165 or (resid 1166...

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111(chain A and (resid 1162 through 1172 or (resid 1173...A1162 - 1172
121(chain A and (resid 1162 through 1172 or (resid 1173...A1173
131(chain A and (resid 1162 through 1172 or (resid 1173...A1162 - 1
141(chain A and (resid 1162 through 1172 or (resid 1173...A1162 - 1
151(chain A and (resid 1162 through 1172 or (resid 1173...A1162 - 1
161(chain A and (resid 1162 through 1172 or (resid 1173...A1162 - 1
211(chain B and (resid 1162 through 1165 or (resid 1166...B1162 - 1165
221(chain B and (resid 1162 through 1165 or (resid 1166...B1166
231(chain B and (resid 1162 through 1165 or (resid 1166...B1162 - 1
241(chain B and (resid 1162 through 1165 or (resid 1166...B1162 - 1
251(chain B and (resid 1162 through 1165 or (resid 1166...B1162 - 1
261(chain B and (resid 1162 through 1165 or (resid 1166...B1162 - 1

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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
Fragment: (UNP residues 1159-1519)-linker-(UNP residues 1581-1666)
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) / Strain (production host): BL21(DE3) / 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-6YI / (4S)-N-(3H-indazol-4-yl)-3-[1-(4-methoxyphenyl)cyclopentyl]carbonyl-1,1-bis(oxidanylidene)-1,3-thiazolidine-4-carboxamide


Mass: 482.552 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H26N4O5S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 507 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.96 Å3/Da / Density % sol: 58.5 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 12% PEG3350, 0.1 M HEPES (pH 7.0)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS VII / Detector: IMAGE PLATE / Date: Oct 2, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.1→19.72 Å / Num. obs: 66772 / % possible obs: 94.8 % / Redundancy: 3.928 % / Biso Wilson estimate: 35.06 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.128 / Rrim(I) all: 0.148 / Χ2: 0.954 / Net I/σ(I): 8.75 / Num. measured all: 262252
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
2.1-2.233.8341.3121.013897711258101660.5011.52190.3
2.23-2.383.9470.8781.68391961061199300.6751.01693.6
2.38-2.563.9810.5762.3337268991993620.8270.66694.4
2.56-2.83.9770.3623.7334234901986090.9190.41895.5
2.8-3.133.9730.187.1831763831779950.9760.20896.1
3.13-3.63.9530.09313.3527878727270530.9930.10797
3.6-4.373.8930.05322.8823574620860560.9970.06297.6
4.37-6.033.9210.04226.7218615483847480.9980.04898.1
6.03-19.723.7670.03630.2810747298228530.9980.04395.7

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHENIX1.19.1_4122refinement
PDB_EXTRACT3.27data extraction
CrystalCleardata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4bhw

4bhw


Resolution: 2.1→19.72 Å / SU ML: 0.31 / Cross valid method: THROUGHOUT / σ(F): 1.91 / Phase error: 27.55 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.235 3320 4.98 %
Rwork0.1993 63315 -
obs0.2011 66635 95.27 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 130.04 Å2 / Biso mean: 46.9311 Å2 / Biso min: 20.55 Å2
Refinement stepCycle: final / Resolution: 2.1→19.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6970 0 74 507 7551
Biso mean--42.62 44.81 -
Num. residues----874
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2658X-RAY DIFFRACTION7.078TORSIONAL
12B2658X-RAY DIFFRACTION7.078TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 24

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.1-2.130.40481200.34422432255289
2.13-2.160.33961470.30072623277093
2.16-2.20.35171140.29582569268393
2.2-2.230.43511320.36662554268693
2.23-2.270.42921330.38312650278394
2.27-2.310.39121210.33732526264791
2.31-2.360.30081280.27352563269194
2.36-2.410.30761330.24942658279194
2.41-2.460.31091400.24552606274695
2.46-2.520.29081430.23332626276995
2.52-2.580.27741460.22032649279595
2.58-2.650.23931320.22042606273896
2.65-2.730.24781360.2232688282495
2.73-2.810.25991360.22822591272796
2.81-2.910.26721570.21492703286096
2.91-3.030.28431270.19962671279896
3.03-3.170.22281380.1942665280397
3.17-3.330.2281580.19212702286097
3.33-3.540.20841250.18082669279497
3.54-3.810.19251470.16522733288098
3.81-4.190.19131630.15372680284398
4.19-4.790.17411480.14852728287698
4.79-6.010.18341550.16132717287299
6.01-19.720.19821410.16312706284797
Refinement TLS params.Method: refined / Origin x: -22.175 Å / Origin y: 7.3542 Å / Origin z: -0.4811 Å
111213212223313233
T0.2539 Å2-0.0251 Å2-0.0063 Å2-0.292 Å2-0.0168 Å2--0.2488 Å2
L0.2569 °2-0.0757 °2-0.0356 °2-0.447 °2-0.2742 °2--0.4076 °2
S0.0025 Å °0.0073 Å °0.0159 Å °-0.0742 Å °0.0527 Å °-0.0243 Å °0.0033 Å °-0.0935 Å °-0.057 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1162 - 1
2X-RAY DIFFRACTION1allB1162 - 1
3X-RAY DIFFRACTION1allS1 - 507

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