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

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Basic information

Entry
Database: PDB / ID: 7vhz
TitleCrystal structure of EP300 HAT domain in complex with compound 7
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 / histone H3K122 acetyltransferase activity / peptide butyryltransferase activity ...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 / histone H3K122 acetyltransferase activity / 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 / NGF-stimulated transcription / NFE2L2 regulating inflammation associated genes / histone H3K18 acetyltransferase activity / N-terminal peptidyl-lysine acetylation / histone H3K27 acetyltransferase activity / 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 / regulation of glycolytic process / NOTCH3 Intracellular Domain Regulates Transcription / 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 / Formation of paraxial mesoderm / positive regulation of transforming growth factor beta receptor signaling pathway / acetyltransferase activity / FOXO-mediated transcription of cell death genes / PI5P Regulates TP53 Acetylation / fat cell differentiation / 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 / pre-mRNA intronic binding / Attenuation phase / somitogenesis / negative regulation of protein-containing complex assembly / positive regulation of DNA-binding transcription factor activity / positive regulation of T-helper 17 cell lineage commitment / cellular response to nutrient levels / histone acetyltransferase activity / 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 / 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 / transcription initiation-coupled chromatin remodeling / lung development / 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-6TI / 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: 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

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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)106,06910
Polymers104,8112
Non-polymers1,2578
Water9,710539
1
A: Histone acetyltransferase p300
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,0345
Polymers52,4061
Non-polymers6294
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Histone acetyltransferase p300
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,0345
Polymers52,4061
Non-polymers6294
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)43.676, 89.219, 91.132
Angle α, β, γ (deg.)114.990, 95.330, 92.020
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 1162 through 1179 or (resid 1180...
21(chain B and (resid 1162 through 1166 or (resid 1167...

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111(chain A and (resid 1162 through 1179 or (resid 1180...A1162 - 1179
121(chain A and (resid 1162 through 1179 or (resid 1180...A1180 - 1182
131(chain A and (resid 1162 through 1179 or (resid 1180...A1162 - 1
141(chain A and (resid 1162 through 1179 or (resid 1180...A1162 - 1
151(chain A and (resid 1162 through 1179 or (resid 1180...A1162 - 1
161(chain A and (resid 1162 through 1179 or (resid 1180...A1162 - 1
211(chain B and (resid 1162 through 1166 or (resid 1167...B1162 - 1166
221(chain B and (resid 1162 through 1166 or (resid 1167...B1167
231(chain B and (resid 1162 through 1166 or (resid 1167...B1162 - 1
241(chain B and (resid 1162 through 1166 or (resid 1167...B1162 - 1
251(chain B and (resid 1162 through 1166 or (resid 1167...B1162 - 1
261(chain B and (resid 1162 through 1166 or (resid 1167...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-6TI / (2R)-N-(2H-indazol-4-yl)-1-[1-(4-methoxyphenyl)cyclopentyl]carbonyl-pyrrolidine-2-carboxamide


Mass: 432.515 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H28N4O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 539 / 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: 3.05 Å3/Da / Density % sol: 59.64 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 16% PEG3350, 0.1 M HEPES (pH 7.0)

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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: Jun 8, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 2→19.98 Å / Num. obs: 78731 / % possible obs: 94.2 % / Redundancy: 1.837 % / Biso Wilson estimate: 37.98 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.044 / Rrim(I) all: 0.062 / Χ2: 0.965 / Net I/σ(I): 10.72 / Num. measured all: 144642
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
2-2.121.7790.5771.232215713492124560.5640.81592.3
2.12-2.271.9120.3562.192264012697118430.7740.50393.3
2.27-2.451.8960.1963.752127511808112200.9190.27795
2.45-2.681.860.1066.441950310882104840.9720.15196.3
2.68-31.7630.05910.616722981494840.9910.08496.6
3-3.461.8030.03417.7215038870183420.9960.04895.9
3.46-4.231.7580.02425.7512138734169060.9980.03494.1
4.23-5.961.9380.0232.6410193567452600.9980.02892.7
5.96-19.981.8190.02134.694976316827360.9990.0386.4

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHENIX1.19_4092refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4bhw

4bhw


Resolution: 2→19.98 Å / SU ML: 0.25 / Cross valid method: THROUGHOUT / σ(F): 1.95 / Phase error: 23.98 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2188 3904 4.96 %
Rwork0.191 74747 -
obs0.1924 78651 94.37 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 122.66 Å2 / Biso mean: 48.9303 Å2 / Biso min: 22.99 Å2
Refinement stepCycle: final / Resolution: 2→19.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6970 0 70 539 7579
Biso mean--39.93 48.08 -
Num. residues----878
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2692X-RAY DIFFRACTION6.177TORSIONAL
12B2692X-RAY DIFFRACTION6.177TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 28

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2-2.030.34641300.33092569269991
2.03-2.050.31091440.3052618276293
2.05-2.080.29221420.29532677281992
2.08-2.110.36371180.29062580269893
2.11-2.140.31421320.28332615274793
2.14-2.170.30681540.27312664281893
2.17-2.20.31971300.26392624275493
2.2-2.240.29041280.25842644277293
2.24-2.280.25251380.23742705284394
2.28-2.320.26511240.23782671279595
2.32-2.360.24321360.22582680281695
2.36-2.410.24811380.22912737287595
2.41-2.460.2621470.22882668281596
2.46-2.520.25111570.21382716287397
2.52-2.580.26431330.21342772290597
2.58-2.650.22731530.2172710286396
2.65-2.730.22481480.20832752290097
2.73-2.820.26131360.21462686282296
2.82-2.920.23841480.20312777292597
2.92-3.040.24571440.19412690283497
3.04-3.170.20791400.18682759289996
3.17-3.340.23391580.19742717287596
3.34-3.550.23681180.18362686280496
3.55-3.820.17511400.16782684282495
3.82-4.20.1771570.15352641279893
4.2-4.80.16061340.14322668280294
4.8-6.020.18381490.16222581273092
6.02-19.980.18681280.15052456258487
Refinement TLS params.Method: refined / Origin x: -22.3871 Å / Origin y: 3.4433 Å / Origin z: -5.2663 Å
111213212223313233
T0.2101 Å2-0.0263 Å2-0.0101 Å2-0.255 Å2-0.0127 Å2--0.2489 Å2
L0.1082 °2-0.0996 °2-0.0302 °2-0.4987 °2-0.328 °2--0.4588 °2
S-0.0228 Å °-0.0191 Å °0.0063 Å °-0.0813 Å °0.0776 Å °-0.0164 Å °0.0217 Å °-0.1027 Å °-0.0535 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1162 - 1
2X-RAY DIFFRACTION1allB1162 - 1
3X-RAY DIFFRACTION1allS1 - 552

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