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

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Basic information

Entry
Database: PDB / ID: 5gsa
TitleEED in complex with an allosteric PRC2 inhibitor
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


regulation of kidney development / hepatocyte homeostasis / cellular response to trichostatin A / regulation of gliogenesis / [histone H3]-lysine27 N-trimethyltransferase / negative regulation of striated muscle cell differentiation / negative regulation of keratinocyte differentiation / histone H3K27 trimethyltransferase activity / negative regulation of retinoic acid receptor signaling pathway / primary miRNA binding ...regulation of kidney development / hepatocyte homeostasis / cellular response to trichostatin A / regulation of gliogenesis / [histone H3]-lysine27 N-trimethyltransferase / negative regulation of striated muscle cell differentiation / negative regulation of keratinocyte differentiation / histone H3K27 trimethyltransferase activity / negative regulation of retinoic acid receptor signaling pathway / primary miRNA binding / skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration / response to tetrachloromethane / cerebellar cortex development / 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 / G1 to G0 transition / : / lncRNA binding / positive regulation of dendrite development / histone H3 methyltransferase activity / negative regulation of gene expression, epigenetic / negative regulation of G1/S transition of mitotic cell cycle / spinal cord development / 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 / pericentric heterochromatin / enzyme activator activity / heterochromatin formation / positive regulation of epithelial to mesenchymal transition / ribonucleoprotein complex binding / keratinocyte differentiation / protein localization to chromatin / B cell differentiation / transcription corepressor binding / PRC2 methylates histones and DNA / Regulation of PTEN gene transcription / Defective pyroptosis / liver regeneration / stem cell differentiation / promoter-specific chromatin binding / hippocampus development / G1/S transition of mitotic cell cycle / positive regulation of MAP kinase activity / protein modification process / positive regulation of protein serine/threonine kinase activity / regulation of circadian rhythm / chromatin DNA binding / PKMTs methylate histone lysines / cellular response to hydrogen peroxide / positive regulation of GTPase activity / Activation of anterior HOX genes in hindbrain development during early embryogenesis / HCMV Early Events / transcription corepressor activity / rhythmic process / response to estradiol / chromosome / chromatin organization / Oxidative Stress Induced Senescence / chromosome, telomeric region / RNA polymerase II cis-regulatory region sequence-specific DNA binding / negative regulation of DNA-templated transcription / synapse / chromatin binding / positive regulation of cell population proliferation / chromatin / regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / nucleoplasm / identical protein binding / nucleus / cytosol
Similarity search - Function
EZH2, SET domain / : / Ezh2, MCSS 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 / Tesmin/TSO1-like CXC domain ...EZH2, SET domain / : / Ezh2, MCSS 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 / Tesmin/TSO1-like CXC domain / Tesmin/TSO1-like CXC domain / Histone-lysine N-methyltransferase EZH1/2-like / CXC domain / CXC domain profile. / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain superfamily / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SET domain / SANT/Myb domain / SET domain profile. / SET domain / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Mainly Beta
Similarity search - Domain/homology
Chem-73K / Polycomb protein EED / Histone-lysine N-methyltransferase EZH2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.49 Å
AuthorsZhao, K. / Zhao, M. / Luo, X. / Zhang, H.
CitationJournal: Nat. Chem. Biol. / Year: 2017
Title: An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of
Authors: Qi, W. / Zhao, K. / Gu, J. / Huang, Y. / Wang, Y. / Zhang, H. / Zhang, M. / Zhang, J. / Yu, Z. / Li, L. / Teng, L. / Chuai, S. / Zhang, C. / Zhao, M. / Chan, H. / Chen, Z. / Fang, D. / Fei, ...Authors: Qi, W. / Zhao, K. / Gu, J. / Huang, Y. / Wang, Y. / Zhang, H. / Zhang, M. / Zhang, J. / Yu, Z. / Li, L. / Teng, L. / Chuai, S. / Zhang, C. / Zhao, M. / Chan, H. / Chen, Z. / Fang, D. / Fei, Q. / Feng, L. / Feng, L. / Gao, Y. / Ge, H. / Ge, X. / Li, G. / Lingel, A. / Lin, Y. / Liu, Y. / Luo, F. / Shi, M. / Wang, L. / Wang, Z. / Yu, Y. / Zeng, J. / Zeng, C. / Zhang, L. / Zhang, Q. / Zhou, S. / Oyang, C. / Atadja, P. / Li, E.
History
DepositionAug 15, 2016Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 1, 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)92,6966
Polymers91,9574
Non-polymers7392
Water3,243180
1
A: Polycomb protein EED
C: Histone-lysine N-methyltransferase EZH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,3483
Polymers45,9782
Non-polymers3691
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2910 Å2
ΔGint-13 kcal/mol
Surface area15890 Å2
MethodPISA
2
B: Polycomb protein EED
D: Histone-lysine N-methyltransferase EZH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,3483
Polymers45,9782
Non-polymers3691
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2860 Å2
ΔGint-16 kcal/mol
Surface area16010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)93.793, 177.908, 50.532
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 / 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 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: Q15910, histone-lysine N-methyltransferase
#3: Chemical ChemComp-73K / N-(furan-2-ylmethyl)-8-(4-methylsulfonylphenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine


Mass: 369.398 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H15N5O3S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 180 / 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: 2.29 Å3/Da / Density % sol: 46.34 %
Crystal growTemperature: 293 K / Method: evaporation / pH: 8 / Details: 0.1 M TRIS, 16% PEG 8000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.9793 Å
DetectorType: MAR CCD 130 mm / Detector: CCD / Date: Apr 16, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.49→50 Å / Num. obs: 30316 / % possible obs: 99.6 % / Redundancy: 6.3 % / Biso Wilson estimate: 48.99 Å2 / Rmerge(I) obs: 0.117 / Net I/av σ(I): 15.237 / Net I/σ(I): 9.9
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.5-2.596.40.535199.8
2.59-2.696.40.422199.9
2.69-2.826.40.3341100
2.82-2.966.40.259199.8
2.96-3.156.40.188199.6
3.15-3.396.40.139199.2
3.39-3.736.20.111199.3
3.73-4.2760.089199.1
4.27-5.385.90.07199.3
5.38-506.50.062199.6

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
BUSTER-TNT2.11.5refinement
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2QXV

2qxv


Resolution: 2.49→43.94 Å / Cor.coef. Fo:Fc: 0.9185 / Cor.coef. Fo:Fc free: 0.8708 / SU R Cruickshank DPI: 0.586 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.659 / SU Rfree Blow DPI: 0.296 / SU Rfree Cruickshank DPI: 0.296
RfactorNum. reflection% reflectionSelection details
Rfree0.255 1531 5.06 %RANDOM
Rwork0.1817 ---
obs0.1854 30258 99.19 %-
Displacement parametersBiso max: 125.91 Å2 / Biso mean: 41.73 Å2 / Biso min: 14.69 Å2
Baniso -1Baniso -2Baniso -3
1--20.8879 Å20 Å20 Å2
2--11.023 Å20 Å2
3---9.8649 Å2
Refine analyzeLuzzati coordinate error obs: 0.286 Å
Refinement stepCycle: final / Resolution: 2.49→43.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6354 0 52 180 6586
Biso mean--38.47 39.14 -
Num. residues----780
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2304SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes170HARMONIC2
X-RAY DIFFRACTIONt_gen_planes941HARMONIC5
X-RAY DIFFRACTIONt_it6569HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion831SEMIHARMONIC5
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_contact7543SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6569HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg8892HARMONIC21.17
X-RAY DIFFRACTIONt_omega_torsion3.31
X-RAY DIFFRACTIONt_other_torsion19.47
LS refinement shellResolution: 2.49→2.58 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.299 139 4.94 %
Rwork0.2157 2673 -
all0.2196 2812 -
obs--99.19 %

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