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- PDB-5h14: EED in complex with an allosteric PRC2 inhibitor EED666 -

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Basic information

Entry
Database: PDB / ID: 5h14
TitleEED in complex with an allosteric PRC2 inhibitor EED666
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 / response to tetrachloromethane / negative regulation of keratinocyte differentiation / histone H3K27 trimethyltransferase activity / negative regulation of retinoic acid receptor signaling pathway ...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 / response to tetrachloromethane / negative regulation of keratinocyte differentiation / histone H3K27 trimethyltransferase activity / negative regulation of retinoic acid receptor signaling pathway / cerebellar cortex development / primary miRNA binding / regulation of adaxial/abaxial pattern formation / skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration / regulatory ncRNA-mediated heterochromatin formation / histone H3K27 methyltransferase activity / sex chromatin / positive regulation of cell cycle G1/S phase transition / facultative heterochromatin formation / genomic imprinting / ESC/E(Z) complex / negative regulation of stem cell differentiation / protein-lysine N-methyltransferase activity / cardiac muscle hypertrophy in response to stress / chromatin silencing complex / pronucleus / positive regulation of dendrite development / G1 to G0 transition / histone H3 methyltransferase activity / histone methyltransferase activity / DNA methylation-dependent constitutive heterochromatin formation / negative regulation of G1/S transition of mitotic cell cycle / spinal cord development / lncRNA binding / negative regulation of gene expression, epigenetic / synaptic transmission, GABAergic / Transcriptional Regulation by E2F6 / : / positive regulation of MAP kinase activity / oligodendrocyte differentiation / negative regulation of transcription elongation by RNA polymerase II / positive regulation of GTPase activity / positive regulation of protein serine/threonine kinase activity / positive regulation of epithelial to mesenchymal transition / ribonucleoprotein complex binding / subtelomeric heterochromatin formation / pericentric heterochromatin / RNA polymerase II core promoter sequence-specific DNA binding / nucleosome binding / keratinocyte differentiation / protein localization to chromatin / liver regeneration / negative regulation of cytokine production involved in inflammatory response / cellular response to leukemia inhibitory factor / B cell differentiation / Regulation of PTEN gene transcription / transcription corepressor binding / PRC2 methylates histones and DNA / Defective pyroptosis / hippocampus development / stem cell differentiation / promoter-specific chromatin binding / enzyme activator activity / G1/S transition of mitotic cell cycle / regulation of circadian rhythm / chromatin DNA binding / protein modification process / PKMTs methylate histone lysines / Activation of anterior HOX genes in hindbrain development during early embryogenesis / cellular response to hydrogen peroxide / HCMV Early Events / rhythmic process / transcription corepressor activity / response to estradiol / heterochromatin formation / chromosome / chromatin organization / Oxidative Stress Induced Senescence / histone binding / 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 / 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 / WD domain, G-beta repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Mainly Beta
Similarity search - Domain/homology
Chem-LQB / 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.
CitationJournal: 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.
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
Revision 1.2Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)92,8388
Polymers91,9574
Non-polymers8814
Water7,422412
1
A: Polycomb protein EED
D: Histone-lysine N-methyltransferase EZH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,4194
Polymers45,9782
Non-polymers4402
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2920 Å2
ΔGint-15 kcal/mol
Surface area16560 Å2
MethodPISA
2
B: Polycomb protein EED
C: Histone-lysine N-methyltransferase EZH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,4194
Polymers45,9782
Non-polymers4402
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2860 Å2
ΔGint-14 kcal/mol
Surface area15770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)93.758, 178.353, 50.545
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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-LQB / 2-[3-(3,5-dimethylpyrazol-1-yl)-4-nitro-phenyl]-3,4-dihydro-1H-isoquinoline


Mass: 348.398 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H20N4O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 412 / Source method: isolated from a natural source / Formula: H2O
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: 2.3 Å3/Da / Density % sol: 46.47 %
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: 0.979467 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 13, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979467 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 67346 / % possible obs: 99.5 % / Redundancy: 6.7 % / Biso Wilson estimate: 23.67 Å2 / Rmerge(I) obs: 0.083 / Net I/av σ(I): 23 / Net I/σ(I): 13
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
1.9-1.976.80.5311100
1.97-2.056.80.348199.8
2.05-2.146.80.252199.6
2.14-2.256.80.19199.6
2.25-2.396.70.161199.5
2.39-2.586.70.139199.4
2.58-2.846.60.113199.2
2.84-3.256.40.086199.4
3.25-4.096.60.055199.5
4.09-506.80.043198.9

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Processing

Software
NameVersionClassification
HKL-2000data scaling
BUSTER2.11.5refinement
PDB_EXTRACT3.2data extraction
MOLREPphasing
HKLdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2QXV

2qxv


Resolution: 1.9→40.27 Å / Cor.coef. Fo:Fc: 0.9348 / Cor.coef. Fo:Fc free: 0.9187 / SU R Cruickshank DPI: 0.151 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.155 / SU Rfree Blow DPI: 0.136 / SU Rfree Cruickshank DPI: 0.135
RfactorNum. reflection% reflectionSelection details
Rfree0.2225 3406 5.06 %RANDOM
Rwork0.1916 ---
obs0.1931 67285 99.24 %-
Displacement parametersBiso max: 109.76 Å2 / Biso mean: 30.78 Å2 / Biso min: 4.46 Å2
Baniso -1Baniso -2Baniso -3
1--11.3248 Å20 Å20 Å2
2--6.2694 Å20 Å2
3---5.0554 Å2
Refine analyzeLuzzati coordinate error obs: 0.226 Å
Refinement stepCycle: final / Resolution: 1.9→40.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6355 0 64 412 6831
Biso mean--45.87 37.38 -
Num. residues----780
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2326SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes169HARMONIC2
X-RAY DIFFRACTIONt_gen_planes948HARMONIC5
X-RAY DIFFRACTIONt_it6601HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion834SEMIHARMONIC5
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_contact7474SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6601HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg8930HARMONIC21.06
X-RAY DIFFRACTIONt_omega_torsion3.62
X-RAY DIFFRACTIONt_other_torsion17.51
LS refinement shellResolution: 1.9→1.95 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2557 251 5.27 %
Rwork0.2297 4509 -
all0.231 4760 -
obs--99.24 %

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