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- PDB-7lje: Discovery of Spirohydantoins as Selective, Orally Bioavailable In... -

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Basic information

Entry
Database: PDB / ID: 7lje
TitleDiscovery of Spirohydantoins as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases
ComponentsHistone acetyltransferase p300
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / histone acetylation / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


behavioral defense response / protein propionyltransferase activity / peptidyl-lysine propionylation / histone lactyltransferase activity / peptidyl-lysine crotonylation / peptidyl-lysine butyrylation / histone butyryltransferase activity / histone H3K122 acetyltransferase activity / swimming / peptide butyryltransferase activity ...behavioral defense response / protein propionyltransferase activity / peptidyl-lysine propionylation / histone lactyltransferase 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 / NOTCH2 intracellular domain regulates transcription / lysine N-acetyltransferase activity, acting on acetyl phosphate as donor / peptidyl-lysine acetylation / histone H3 acetyltransferase activity / histone H4 acetyltransferase activity / cellular response to L-leucine / internal peptidyl-lysine acetylation / NFE2L2 regulating ER-stress associated genes / peptide N-acetyltransferase activity / STAT3 nuclear events downstream of ALK signaling / acetylation-dependent protein binding / Activation of the TFAP2 (AP-2) family of transcription factors / NFE2L2 regulating inflammation associated genes / NGF-stimulated transcription / histone H3K27 acetyltransferase activity / histone H3K18 acetyltransferase activity / Polo-like kinase mediated events / N-terminal peptidyl-lysine acetylation / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / NFE2L2 regulates pentose phosphate pathway genes / regulation of androgen receptor signaling pathway / NFE2L2 regulating MDR associated enzymes / positive regulation by host of viral transcription / regulation of mitochondrion organization / face morphogenesis / Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells / RUNX3 regulates NOTCH signaling / NOTCH4 Intracellular Domain Regulates Transcription / Regulation of FOXO transcriptional activity by acetylation / Regulation of gene expression by Hypoxia-inducible Factor / Nuclear events mediated by NFE2L2 / Regulation of NFE2L2 gene expression / NOTCH3 Intracellular Domain Regulates Transcription / regulation of glycolytic process / TRAF6 mediated IRF7 activation / platelet formation / megakaryocyte development / peptide-lysine-N-acetyltransferase activity / nuclear androgen receptor binding / NFE2L2 regulating anti-oxidant/detoxification enzymes / regulation of tubulin deacetylation / macrophage derived foam cell differentiation / FOXO-mediated transcription of cell death genes / NFE2L2 regulating tumorigenic genes / internal protein amino acid acetylation / STAT family protein binding / acyltransferase activity / protein acetylation / fat cell differentiation / Formation of paraxial mesoderm / RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known / positive regulation of transforming growth factor beta receptor signaling pathway / PI5P Regulates TP53 Acetylation / Zygotic genome activation (ZGA) / acetyltransferase activity / stimulatory C-type lectin receptor signaling pathway / cellular response to nutrient levels / RUNX3 regulates p14-ARF / NF-kappaB binding / histone acetyltransferase complex / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / canonical NF-kappaB signal transduction / Attenuation phase / negative regulation of protein-containing complex assembly / negative regulation of gluconeogenesis / pre-mRNA intronic binding / somitogenesis / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / regulation of cellular response to heat / skeletal muscle tissue development / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / histone acetyltransferase activity / histone acetyltransferase / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / transcription initiation-coupled chromatin remodeling / 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 / transcription coregulator binding
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-Y2P / Histone acetyltransferase p300
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.607 Å
AuthorsJakob, C.G.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2021
Title: Discovery of spirohydantoins as selective, orally bioavailable inhibitors of p300/CBP histone acetyltransferases.
Authors: Ji, Z. / Clark, R.F. / Bhat, V. / Matthew Hansen, T. / Lasko, L.M. / Bromberg, K.D. / Manaves, V. / Algire, M. / Martin, R. / Qiu, W. / Torrent, M. / Jakob, C.G. / Liu, H. / Cole, P.A. / ...Authors: Ji, Z. / Clark, R.F. / Bhat, V. / Matthew Hansen, T. / Lasko, L.M. / Bromberg, K.D. / Manaves, V. / Algire, M. / Martin, R. / Qiu, W. / Torrent, M. / Jakob, C.G. / Liu, H. / Cole, P.A. / Marmorstein, R. / Kesicki, E.A. / Lai, A. / Michaelides, M.R.
History
DepositionJan 29, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 17, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 31, 2021Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.title
Revision 1.2Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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
C: Histone acetyltransferase p300
D: Histone acetyltransferase p300
hetero molecules


Theoretical massNumber of molelcules
Total (without water)163,5188
Polymers161,0444
Non-polymers2,4744
Water8,881493
1
A: Histone acetyltransferase p300
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,8802
Polymers40,2611
Non-polymers6191
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Histone acetyltransferase p300
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,8802
Polymers40,2611
Non-polymers6191
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Histone acetyltransferase p300
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,8802
Polymers40,2611
Non-polymers6191
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Histone acetyltransferase p300
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,8802
Polymers40,2611
Non-polymers6191
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)151.294, 81.491, 124.095
Angle α, β, γ (deg.)90.000, 117.310, 90.000
Int Tables number5
Space group name H-MC121

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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: 40261.000 Da / Num. of mol.: 4 / Fragment: acetyltransferase domain (UNP residues 1287-1666)
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-Y2P / 2-[4-[(3'R,4S)-3'-fluoro-1-[2-[(4-fluorophenyl)methyl-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]amino]-2-oxo-ethyl]-2,5-dioxo-spiro[imidazolidine-4,1'-indane]-5'-yl]pyrazol-1-yl]-N-methyl-acetamide


Mass: 618.554 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C29H27F5N6O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 493 / 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: 2.11 Å3/Da / Density % sol: 41.72 %
Crystal growTemperature: 290 K / Method: vapor diffusion / pH: 5.5
Details: 25% PEG 3350, 0.2 M Ammonium Acetate, 0.1 M Bis-Tris HCl pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 15, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.607→74.58 Å / Num. obs: 40754 / % possible obs: 99.1 % / Redundancy: 3.4 % / Biso Wilson estimate: 61.43 Å2 / Rmerge(I) obs: 0.106 / Net I/σ(I): 7.2
Reflection shellResolution: 2.607→2.615 Å / Rmerge(I) obs: 0.654 / Num. unique obs: 378

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
SCALAdata scaling
PHASERphasing
BUSTER2.11.8 (11-DEC-2020)refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5KJ2

5kj2


Resolution: 2.607→74.58 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.909 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.357
RfactorNum. reflection% reflectionSelection details
Rfree0.2651 1977 4.85 %RANDOM
Rwork0.2115 ---
obs0.2141 40753 99.1 %-
Displacement parametersBiso max: 176.85 Å2 / Biso mean: 44.98 Å2 / Biso min: 15.38 Å2
Baniso -1Baniso -2Baniso -3
1--0.176 Å20 Å2-3.3167 Å2
2--3.784 Å20 Å2
3----3.6079 Å2
Refine analyzeLuzzati coordinate error obs: 0.34 Å
Refinement stepCycle: final / Resolution: 2.607→74.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10522 0 176 493 11191
Biso mean--40.75 42.2 -
Num. residues----1286
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3861SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1948HARMONIC5
X-RAY DIFFRACTIONt_it11016HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1353SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact8435SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d11016HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg14939HARMONIC20.97
X-RAY DIFFRACTIONt_omega_torsion3.08
X-RAY DIFFRACTIONt_other_torsion19.05
LS refinement shellResolution: 2.61→2.62 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.3417 42 5.15 %
Rwork0.2835 774 -
all0.2865 816 -
obs--97.01 %

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