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- PDB-5h19: EED in complex with PRC2 allosteric inhibitor EED162 -

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Basic information

Entry
Database: PDB / ID: 5h19
TitleEED in complex with PRC2 allosteric inhibitor EED162
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 / cellular response to trichostatin A / regulation of gliogenesis / negative regulation of striated muscle cell differentiation / regulation of kidney development / [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 / cellular response to trichostatin A / regulation of gliogenesis / negative regulation of striated muscle cell differentiation / regulation of kidney development / [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 / cerebellar cortex development / primary miRNA binding / regulatory ncRNA-mediated heterochromatin formation / skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration / histone H3K27 methyltransferase activity / facultative heterochromatin formation / positive regulation of cell cycle G1/S phase transition / ESC/E(Z) complex / chromatin silencing complex / negative regulation of stem cell differentiation / protein-lysine N-methyltransferase activity / pronucleus / cardiac muscle hypertrophy in response to stress / synaptic transmission, GABAergic / G1 to G0 transition / positive regulation of dendrite development / histone H3 methyltransferase activity / lncRNA binding / DNA methylation-dependent constitutive heterochromatin formation / histone methyltransferase activity / negative regulation of G1/S transition of mitotic cell cycle / spinal cord development / negative regulation of gene expression, epigenetic / Transcriptional Regulation by E2F6 / negative regulation of transcription elongation by RNA polymerase II / negative regulation of cytokine production involved in inflammatory response / subtelomeric heterochromatin formation / pericentric heterochromatin / RNA polymerase II core promoter sequence-specific DNA binding / ribonucleoprotein complex binding / positive regulation of epithelial to mesenchymal transition / nucleosome binding / keratinocyte differentiation / protein localization to chromatin / B cell differentiation / enzyme activator activity / positive regulation of GTPase activity / positive regulation of MAP kinase activity / liver regeneration / hippocampus development / PRC2 methylates histones and DNA / Regulation of PTEN gene transcription / transcription corepressor binding / Defective pyroptosis / positive regulation of protein serine/threonine kinase activity / promoter-specific chromatin binding / stem cell differentiation / regulation of circadian rhythm / protein modification process / PKMTs methylate histone lysines / chromatin DNA binding / 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 / heterochromatin formation / transcription corepressor activity / rhythmic process / response to estradiol / chromatin organization / chromosome / Oxidative Stress Induced Senescence / methylation / histone binding / chromosome, telomeric region / positive regulation of cell migration / RNA polymerase II cis-regulatory region sequence-specific DNA binding / negative regulation of DNA-templated transcription / positive regulation of cell population proliferation / synapse / chromatin binding / regulation of DNA-templated transcription / chromatin / negative regulation of transcription by RNA polymerase II / RNA binding / 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-LQF / Polycomb protein EED / Histone-lysine N-methyltransferase EZH2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsZhao, K. / Zhao, M. / Luo, X. / Zhang, H.
Citation
Journal: PLoS ONE / Year: 2017
Title: Discovery and Molecular Basis of a Diverse Set of Polycomb Repressive Complex 2 Inhibitors Recognition by EED
Authors: Li, L. / Zhang, H. / Zhang, M. / Zhao, M. / Feng, L. / Luo, X. / Gao, Z. / Huang, Y. / Ardayfio, O. / Zhang, J.H. / Lin, Y. / Fan, H. / Mi, Y. / Li, G. / Liu, L. / Feng, L. / Luo, F. / Teng, ...Authors: Li, L. / Zhang, H. / Zhang, M. / Zhao, M. / Feng, L. / Luo, X. / Gao, Z. / Huang, Y. / Ardayfio, O. / Zhang, J.H. / Lin, Y. / Fan, H. / Mi, Y. / Li, G. / Liu, L. / Feng, L. / Luo, F. / Teng, L. / Qi, W. / Ottl, J. / Lingel, A. / Bussiere, D.E. / Yu, Z. / Atadja, P. / Lu, C. / Li, E. / Gu, J. / Zhao, K.
#1: Journal: J. Med. Chem. / Year: 2017
Title: Discovery of First-in-Class, Potent and Orally Bioavailable EED inhibitor with Robust Anti-cancer Efficacy
Authors: Huang, Y. / Zhang, J. / Yu, Z. / Zhang, H. / Wang, Y. / Lingel, A. / Qi, W. / Gu, X.J. / Zhao, K. / Shultz, M.D. / Wang, L. / Fu, X. / Sun, Y. / Zhang, Q. / Jiang, X. / Zhang, J.W. / Zhang, ...Authors: Huang, Y. / Zhang, J. / Yu, Z. / Zhang, H. / Wang, Y. / Lingel, A. / Qi, W. / Gu, X.J. / Zhao, K. / Shultz, M.D. / Wang, L. / Fu, X. / Sun, Y. / Zhang, Q. / Jiang, X. / Zhang, J.W. / 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 8, 2016Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 25, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 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

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Assembly

Deposited unit
A: Polycomb protein EED
B: Histone-lysine N-methyltransferase EZH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,3633
Polymers45,9782
Non-polymers3841
Water4,107228
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2970 Å2
ΔGint-16 kcal/mol
Surface area15520 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.490, 90.990, 179.170
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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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.: 1 / 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.: 1 / Fragment: UNP residues 40-68 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: Q15910, histone-lysine N-methyltransferase
#3: Chemical ChemComp-LQF / 5-(furan-2-ylmethylamino)-9-(phenylmethyl)-8,10-dihydro-7H-[1,2,4]triazolo[3,4-a][2,7]naphthyridine-6-carbonitrile


Mass: 384.434 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H20N6O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 228 / 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: 2.24 Å3/Da / Density % sol: 45.04 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6 / Details: 0.1 M Bis-Tris, 0.2 M MgCl2, 20% PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.979112 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 27, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979112 Å / Relative weight: 1
ReflectionResolution: 1.9→25.19 Å / Num. obs: 33040 / % possible obs: 100 % / Redundancy: 7.3 % / Rmerge(I) obs: 0.134 / Net I/σ(I): 11.8
Reflection shellResolution: 1.905→1.911 Å

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Processing

Software
NameVersionClassification
XSCALEdata scaling
BUSTER2.11.5refinement
PDB_EXTRACT3.2data extraction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2QXV

2qxv


Resolution: 1.9→25.19 Å / Cor.coef. Fo:Fc: 0.9429 / Cor.coef. Fo:Fc free: 0.9216 / SU R Cruickshank DPI: 0.141 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.146 / SU Rfree Blow DPI: 0.133 / SU Rfree Cruickshank DPI: 0.132
RfactorNum. reflection% reflectionSelection details
Rfree0.2154 1668 5.09 %RANDOM
Rwork0.1766 ---
obs0.1786 32764 99.18 %-
Displacement parametersBiso max: 104.96 Å2 / Biso mean: 27.53 Å2 / Biso min: 6.83 Å2
Baniso -1Baniso -2Baniso -3
1-2.275 Å20 Å20 Å2
2---6.4862 Å20 Å2
3---4.2113 Å2
Refine analyzeLuzzati coordinate error obs: 0.19 Å
Refinement stepCycle: final / Resolution: 1.9→25.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3125 0 29 228 3382
Biso mean--22.69 35.82 -
Num. residues----384
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1142SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes83HARMONIC2
X-RAY DIFFRACTIONt_gen_planes466HARMONIC5
X-RAY DIFFRACTIONt_it3246HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion411SEMIHARMONIC5
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_contact3679SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3246HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg4391HARMONIC21.05
X-RAY DIFFRACTIONt_omega_torsion3.54
X-RAY DIFFRACTIONt_other_torsion16.26
LS refinement shellResolution: 1.9→1.96 Å / Total num. of bins used: 16
RfactorNum. reflection% reflection
Rfree0.3041 149 5.43 %
Rwork0.2156 2597 -
all0.2203 2746 -
obs--99.18 %

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