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- PDB-5u62: Crystal structure of EED in complex with H3K27Me3 peptide and 6-(... -

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Basic information

Entry
Database: PDB / ID: 5u62
TitleCrystal structure of EED in complex with H3K27Me3 peptide and 6-(benzo[d][1,3]dioxol-4-ylmethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-3-amine
Components
  • Histone-lysine N-methyltransferase EZH2
  • Polycomb protein EED
KeywordsTranscription/Transferase / EED / fragment-based generation / oncology / Transcription-Transferase 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 / facultative heterochromatin formation / histone H3K27 methyltransferase activity / positive regulation of cell cycle G1/S phase transition / chromatin silencing complex / ESC/E(Z) complex / protein-lysine N-methyltransferase activity / negative regulation of stem cell differentiation / pronucleus / cardiac muscle hypertrophy in response to stress / synaptic transmission, GABAergic / lncRNA binding / positive regulation of dendrite development / histone H3 methyltransferase activity / negative regulation of gene expression, epigenetic / G1 to G0 transition / negative regulation of G1/S transition of mitotic cell cycle / spinal cord development / histone methyltransferase activity / Transcriptional Regulation by E2F6 / negative regulation of transcription elongation by RNA polymerase II / subtelomeric heterochromatin formation / negative regulation of cytokine production involved in inflammatory response / RNA polymerase II core promoter sequence-specific DNA binding / pericentric heterochromatin / ribonucleoprotein complex binding / heterochromatin formation / positive regulation of epithelial to mesenchymal transition / nucleosome binding / keratinocyte differentiation / enzyme activator activity / protein localization to chromatin / B cell differentiation / transcription corepressor binding / positive regulation of GTPase activity / PRC2 methylates histones and DNA / Regulation of PTEN gene transcription / Defective pyroptosis / liver regeneration / stem cell differentiation / hippocampus development / promoter-specific chromatin binding / 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 / 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 / methylation / 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 / 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 / : / 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 / SET domain / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SET domain profile. / SET domain / 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-7WD / YTTRIUM (III) ION / Polycomb protein EED / Histone-lysine N-methyltransferase EZH2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 1.9 Å
AuthorsBussiere, D. / Shu, W.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Polycomb Repressive Complex 2 (PRC2) Methyltransferase.
Authors: Lingel, A. / Sendzik, M. / Huang, Y. / Shultz, M.D. / Cantwell, J. / Dillon, M.P. / Fu, X. / Fuller, J. / Gabriel, T. / Gu, J. / Jiang, X. / Li, L. / Liang, F. / McKenna, M. / Qi, W. / Rao, ...Authors: Lingel, A. / Sendzik, M. / Huang, Y. / Shultz, M.D. / Cantwell, J. / Dillon, M.P. / Fu, X. / Fuller, J. / Gabriel, T. / Gu, J. / Jiang, X. / Li, L. / Liang, F. / McKenna, M. / Qi, W. / Rao, W. / Sheng, X. / Shu, W. / Sutton, J. / Taft, B. / Wang, L. / Zeng, J. / Zhang, H. / Zhang, M. / Zhao, K. / Lindvall, M. / Bussiere, D.E.
History
DepositionDec 7, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 11, 2017Provider: repository / Type: Initial release
Revision 1.1Jan 18, 2017Group: Database references
Revision 1.2Jan 25, 2017Group: Database references
Revision 1.3Sep 27, 2017Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.detector
Revision 1.4Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr1_symmetry / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry

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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)93,0289
Polymers92,2154
Non-polymers8135
Water14,412800
1
A: Polycomb protein EED
C: Histone-lysine N-methyltransferase EZH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,6496
Polymers46,1082
Non-polymers5414
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2830 Å2
ΔGint-17 kcal/mol
Surface area15180 Å2
MethodPISA
2
B: Polycomb protein EED
D: Histone-lysine N-methyltransferase EZH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,3793
Polymers46,1082
Non-polymers2711
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2870 Å2
ΔGint-20 kcal/mol
Surface area15570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)92.881, 178.113, 50.480
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

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Protein / Protein/peptide , 2 types, 4 molecules ABCD

#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 K-12 (bacteria) / References: UniProt: O75530
#2: Protein/peptide Histone-lysine N-methyltransferase EZH2 / ENX-1 / Enhancer of zeste homolog 2 / Lysine N-methyltransferase 6


Mass: 3751.344 Da / Num. of mol.: 2 / Fragment: UNP residues 39-68 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: Q15910, histone-lysine N-methyltransferase

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Non-polymers , 4 types, 805 molecules

#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-YT3 / YTTRIUM (III) ION


Mass: 88.906 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Y
#5: Chemical ChemComp-7WD / (6S)-6-[(2H-1,3-benzodioxol-4-yl)methyl]-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-3-amine


Mass: 271.314 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H17N3O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 800 / 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: 2.26 Å3/Da / Density % sol: 45.67 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: Using a PEG/salt combination as a precipitant. Briefly, EED was incubated with 10 mM B-nicotinamide adenine dinucleotide hydrate, 2 mM of a tightly binding proprietary compound, and 0.5 mM ...Details: Using a PEG/salt combination as a precipitant. Briefly, EED was incubated with 10 mM B-nicotinamide adenine dinucleotide hydrate, 2 mM of a tightly binding proprietary compound, and 0.5 mM of a synthesized peptide which comprises the helix on EZH2 which interacts with EED. The crystals were grown using the vapor diffusion method. One uL of the protein mixture was combined with 1 uL of a precipitant comprised of 20% (w/v) PEG3350, 0.2 M potassium iodide, and 0.1M Tris-HCl, pH 8.5, on a cover slip which was suspended over a reservoir comprised of 0.5 mL of precipitant at 18 Celsius and sealed. The crystals grew in 4-6 days at 18 Celsius and then harvested and soaked in defined drops consisting of 30 uL of precipitant and 2 mM of compound for 24 h. Crystals were cryopreserved for data collection using a cryosolution consisting of 30% PEG 400 (v/v), 20% (w/v) PEG 3350, 0.2 M potassium iodide, and 0.1M Tris-HCl, pH 8.5.

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Data collection

DiffractionMean temperature: 270 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jun 22, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→46.44 Å / Num. obs: 65168 / % possible obs: 97.3 % / Redundancy: 5.7 % / Biso Wilson estimate: 25.16 Å2 / Net I/σ(I): 12.4

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Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
XDSdata reduction
SCALAdata scaling
AMoREphasing
RefinementResolution: 1.9→44.94 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.928 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.139 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.154 / SU Rfree Blow DPI: 0.136 / SU Rfree Cruickshank DPI: 0.13
RfactorNum. reflection% reflectionSelection details
Rfree0.208 3159 4.85 %RANDOM
Rwork0.168 ---
obs0.17 65103 97.2 %-
Displacement parametersBiso mean: 31.23 Å2
Baniso -1Baniso -2Baniso -3
1--6.7202 Å20 Å20 Å2
2--3.1434 Å20 Å2
3---3.5768 Å2
Refine analyzeLuzzati coordinate error obs: 0.2 Å
Refinement stepCycle: 1 / Resolution: 1.9→44.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6100 0 48 800 6948
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.016340HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.098602HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2213SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes159HARMONIC2
X-RAY DIFFRACTIONt_gen_planes919HARMONIC5
X-RAY DIFFRACTIONt_it6340HARMONIC20
X-RAY DIFFRACTIONt_nbd2SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.69
X-RAY DIFFRACTIONt_other_torsion16.24
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion817SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies14HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact7580SEMIHARMONIC4
LS refinement shellResolution: 1.9→1.95 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.246 172 4.78 %
Rwork0.231 3425 -
all0.231 3597 -
obs--73.57 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.4852-0.14960.08791.81930.6521.3646-0.0028-0.0151-0.0262-0.01070.0919-0.064-0.00380.0723-0.0891-0.09730.0075-0.005-0.0473-0.0071-0.062925.167165.61730.8577
20.3661-0.0202-0.15292.2340.84671.3813-0.0094-0.00650.0168-0.09730.1074-0.0728-0.08760.0596-0.098-0.0979-0.01730.0134-0.0550.0025-0.076927.736619.873124.2282
32.5117-2.6926-1.41813.1815-1.49910.8336-0.0265-0.0917-0.00590.25290.07840.29840.28390.052-0.05190.029-0.02740.0573-0.0170.0275-0.112117.211656.121413.8901
42.89722.66080.322.1195-0.13050.71370.0064-0.0350.005-0.5452-0.14740.3353-0.3394-0.06620.1410.11010.0641-0.0676-0.05920.0242-0.124116.824127.253612.2109
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }
3X-RAY DIFFRACTION3{ C|* }
4X-RAY DIFFRACTION4{ D|* }

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