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- PDB-5h24: EED in complex with PRC2 allosteric inhibitor compound 8 -

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Basic information

Entry
Database: PDB / ID: 5h24
TitleEED in complex with PRC2 allosteric inhibitor compound 8
Components
  • Histone-lysine N-methyltransferase EZH2
  • Polycomb protein EED
KeywordsTransferase/Transferase Inhibitor / EED / PRC2 / inhibitor / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


hepatocyte homeostasis / regulation of kidney development / cellular response to trichostatin A / regulation of gliogenesis / negative regulation of striated muscle cell differentiation / [histone H3]-lysine27 N-trimethyltransferase / negative regulation of keratinocyte differentiation / histone H3K27 trimethyltransferase activity / negative regulation of retinoic acid receptor signaling pathway / response to tetrachloromethane ...hepatocyte homeostasis / regulation of kidney development / cellular response to trichostatin A / regulation of gliogenesis / negative regulation of striated muscle cell differentiation / [histone H3]-lysine27 N-trimethyltransferase / negative regulation of keratinocyte differentiation / histone H3K27 trimethyltransferase activity / negative regulation of retinoic acid receptor signaling pathway / response to tetrachloromethane / skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration / cerebellar cortex development / primary miRNA binding / regulatory ncRNA-mediated heterochromatin formation / histone H3K27 methyltransferase activity / facultative heterochromatin formation / positive regulation of cell cycle G1/S phase transition / ESC/E(Z) complex / chromatin silencing complex / protein-lysine N-methyltransferase activity / negative regulation of stem cell differentiation / pronucleus / cardiac muscle hypertrophy in response to stress / synaptic transmission, GABAergic / positive regulation of dendrite development / histone H3 methyltransferase activity / lncRNA binding / negative regulation of G1/S transition of mitotic cell cycle / spinal cord development / G1 to G0 transition / negative regulation of gene expression, epigenetic / histone methyltransferase activity / negative regulation of transcription elongation by RNA polymerase II / Transcriptional Regulation by E2F6 / subtelomeric heterochromatin formation / negative regulation of cytokine production involved in inflammatory response / RNA polymerase II core promoter sequence-specific DNA binding / ribonucleoprotein complex binding / pericentric heterochromatin / positive regulation of epithelial to mesenchymal transition / keratinocyte differentiation / protein localization to chromatin / enzyme activator activity / B cell differentiation / positive regulation of GTPase activity / transcription corepressor binding / PRC2 methylates histones and DNA / Regulation of PTEN gene transcription / Defective pyroptosis / hippocampus development / stem cell differentiation / promoter-specific chromatin binding / liver regeneration / positive regulation of MAP kinase activity / protein modification process / regulation of circadian rhythm / positive regulation of protein serine/threonine kinase activity / chromatin DNA binding / heterochromatin formation / PKMTs methylate histone lysines / cellular response to hydrogen peroxide / Activation of anterior HOX genes in hindbrain development during early embryogenesis / HCMV Early Events / G1/S transition of mitotic cell cycle / transcription corepressor activity / rhythmic process / response to estradiol / chromatin organization / chromosome / Oxidative Stress Induced Senescence / methylation / chromosome, telomeric region / positive regulation of cell migration / RNA polymerase II cis-regulatory region sequence-specific DNA binding / negative regulation of DNA-templated transcription / chromatin binding / positive regulation of cell population proliferation / synapse / regulation of DNA-templated transcription / chromatin / negative regulation of transcription by RNA polymerase II / nucleoplasm / identical protein binding / nucleus / cytosol
Similarity search - Function
EZH2, SET domain / Histone-lysine N-methyltransferase EZH1/EZH2 / Polycomb repressive complex 2 subunit EZH1/EZH2, tri-helical domain / Pre-SET CXC domain / : / WD repeat binding protein EZH2 / Polycomb repressive complex 2 tri-helical domain / CXC domain / Ezh2, MCSS domain / Tesmin/TSO1-like CXC domain ...EZH2, SET domain / Histone-lysine N-methyltransferase EZH1/EZH2 / Polycomb repressive complex 2 subunit EZH1/EZH2, tri-helical domain / Pre-SET CXC domain / : / WD repeat binding protein EZH2 / Polycomb repressive complex 2 tri-helical domain / CXC domain / Ezh2, MCSS domain / Tesmin/TSO1-like CXC domain / Tesmin/TSO1-like CXC domain / CXC domain / Histone-lysine N-methyltransferase EZH1/2-like / CXC domain profile. / : / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain / SET domain superfamily / SET domain profile. / SET domain / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SANT/Myb domain / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Mainly Beta
Similarity search - Domain/homology
Chem-LQG / Polycomb protein EED / Histone-lysine N-methyltransferase EZH2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsZhao, K. / Zhao, M. / Luo, X. / Zhang, H.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery of First-in-Class, Potent, and Orally Bioavailable Embryonic Ectoderm Development (EED) Inhibitor with Robust Anticancer Efficacy
Authors: Huang, Y. / Zhang, J. / Yu, Z. / Zhang, H. / Wang, Y. / Lingel, A. / Qi, W. / Gu, J. / Zhao, K. / Shultz, M.D. / Wang, L. / Fu, X. / Sun, Y. / Zhang, Q. / Jiang, X. / Zhang, J. / Zhang, C. / ...Authors: Huang, Y. / Zhang, J. / Yu, Z. / Zhang, H. / Wang, Y. / Lingel, A. / Qi, W. / Gu, J. / Zhao, K. / Shultz, M.D. / Wang, L. / Fu, X. / Sun, Y. / Zhang, Q. / Jiang, X. / Zhang, J. / Zhang, C. / Li, L. / Zeng, J. / Feng, L. / Zhang, C. / Liu, Y. / Zhang, M. / Zhang, L. / Zhao, M. / Gao, Z. / Liu, X. / Fang, D. / Guo, H. / Mi, Y. / Gabriel, T. / Dillon, M.P. / Atadja, P. / Oyang, C.
History
DepositionOct 14, 2016Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 25, 2017Provider: repository / Type: Initial release
Revision 1.1Apr 5, 2017Group: Database references
Revision 1.2Nov 8, 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: Polycomb protein EED
B: Polycomb protein EED
C: Histone-lysine N-methyltransferase EZH2
D: Histone-lysine N-methyltransferase EZH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,4356
Polymers91,9574
Non-polymers4782
Water1,72996
1
A: Polycomb protein EED
C: Histone-lysine N-methyltransferase EZH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,2183
Polymers45,9782
Non-polymers2391
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2880 Å2
ΔGint-15 kcal/mol
Surface area16080 Å2
MethodPISA
2
B: Polycomb protein EED
D: Histone-lysine N-methyltransferase EZH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,2183
Polymers45,9782
Non-polymers2391
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2900 Å2
ΔGint-13 kcal/mol
Surface area15640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)93.090, 177.800, 50.690
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Polycomb protein EED / hEED / WD protein associating with integrin cytoplasmic tails 1 / WAIT-1


Mass: 42356.246 Da / Num. of mol.: 2 / Fragment: UNP residues 76-441
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EED / Plasmid: pGEX-KG / Production host: Escherichia coli (E. coli) / References: UniProt: O75530
#2: Protein/peptide Histone-lysine N-methyltransferase EZH2 / ENX-1 / Enhancer of zeste homolog 2 / Lysine N-methyltransferase 6


Mass: 3622.164 Da / Num. of mol.: 2 / Fragment: UNP residues 40-68 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: Q15910, histone-lysine N-methyltransferase
#3: Chemical ChemComp-LQG / 5-(furan-2-ylmethylamino)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile


Mass: 239.233 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H9N5O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 96 / Source method: isolated from a natural source / Formula: H2O

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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: 2.28 Å3/Da / Density % sol: 46.07 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 0.1 M Tris, 16% PEG 8000, 10 mM beta-Nicotinamide mononucleotide

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.979305 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 29, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979305 Å / Relative weight: 1
ReflectionResolution: 2.5→29.677 Å / Num. all: 29712 / Num. obs: 29712 / % possible obs: 99.1 % / Redundancy: 3.7 % / Biso Wilson estimate: 45.53 Å2 / Rpim(I) all: 0.092 / Rrim(I) all: 0.183 / Rsym value: 0.157 / Net I/av σ(I): 3.752 / Net I/σ(I): 6.7 / Num. measured all: 110255
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
2.5-2.643.60.5551.31498241970.3290.6480.5552.998.6
2.64-2.83.60.4481.61481940650.2640.5220.4483.698.8
2.8-2.993.70.3162.21406138140.1840.3670.3164.599.4
2.99-3.233.80.223.21333735500.1280.2550.225.899.5
3.23-3.543.80.1534.41259333150.0890.1780.1537.599.9
3.54-3.953.80.1344.81139730200.0780.1550.1348.799.9
3.95-4.563.60.1135.3964826770.0670.1320.1139.999.5
4.56-5.593.80.0985.7852622170.0560.1140.09811.397.1
5.59-7.913.90.0975.9708817970.0560.1120.09710.6100
7.91-29.6773.60.0875.3380410600.0530.1020.08711.397.9

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Processing

Software
NameVersionClassification
SCALA3.3.20data scaling
BUSTER2.10.2refinement
PDB_EXTRACT3.2data extraction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2QXV

2qxv


Resolution: 2.5→29.68 Å / Cor.coef. Fo:Fc: 0.928 / Cor.coef. Fo:Fc free: 0.88 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.621 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.65 / SU Rfree Blow DPI: 0.295 / SU Rfree Cruickshank DPI: 0.298
RfactorNum. reflection% reflectionSelection details
Rfree0.255 1501 5.06 %RANDOM
Rwork0.187 ---
obs0.191 29665 99 %-
Displacement parametersBiso max: 119.57 Å2 / Biso mean: 34.99 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1--9.8459 Å20 Å20 Å2
2--4.8517 Å20 Å2
3---4.9942 Å2
Refine analyzeLuzzati coordinate error obs: 0.3 Å
Refinement stepCycle: final / Resolution: 2.5→29.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6365 0 36 96 6497
Biso mean--26.95 31.53 -
Num. residues----781
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2311SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes170HARMONIC2
X-RAY DIFFRACTIONt_gen_planes978HARMONIC5
X-RAY DIFFRACTIONt_it6561HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion832SEMIHARMONIC5
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_contact7220SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6561HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg8872HARMONIC21.16
X-RAY DIFFRACTIONt_omega_torsion3.26
X-RAY DIFFRACTIONt_other_torsion20.26
LS refinement shellResolution: 2.5→2.59 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.357 140 4.95 %
Rwork0.215 2686 -
all-2826 -
obs--98.2 %

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