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- PDB-5u5t: Crystal structure of EED in complex with H3K27Me3 peptide and 3-(... -

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Basic information

Entry
Database: PDB / ID: 5u5t
TitleCrystal structure of EED in complex with H3K27Me3 peptide and 3-(benzo[d][1,3]dioxol-4-ylmethyl)piperidine-1-carboximidamide
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 / histone H3K27 methyltransferase activity / positive regulation of cell cycle G1/S phase transition / facultative heterochromatin formation / chromatin silencing complex / ESC/E(Z) complex / protein-lysine N-methyltransferase activity / negative regulation of stem cell differentiation / lncRNA binding / pronucleus / cardiac muscle hypertrophy in response to stress / synaptic transmission, GABAergic / G1 to G0 transition / 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 / enzyme activator activity / negative regulation of cytokine production involved in inflammatory response / positive regulation of epithelial to mesenchymal transition / RNA polymerase II core promoter sequence-specific DNA binding / ribonucleoprotein complex binding / pericentric heterochromatin / heterochromatin formation / 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 / promoter-specific chromatin binding / stem cell differentiation / hippocampus development / G1/S transition of mitotic cell cycle / protein modification process / positive regulation of MAP kinase activity / positive regulation of protein serine/threonine kinase activity / regulation of circadian rhythm / chromatin DNA binding / cellular response to hydrogen peroxide / PKMTs methylate histone lysines / 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 / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SET domain superfamily / 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-7W7 / YTTRIUM (III) ION / Polycomb protein EED / Histone-lysine N-methyltransferase EZH2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.6 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 / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _struct_conn.pdbx_dist_value / _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_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)92,9168
Polymers92,2154
Non-polymers7004
Water18,6091033
1
A: Polycomb protein EED
C: Histone-lysine N-methyltransferase EZH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,3693
Polymers46,1082
Non-polymers2611
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2690 Å2
ΔGint-17 kcal/mol
Surface area14880 Å2
MethodPISA
2
B: Polycomb protein EED
D: Histone-lysine N-methyltransferase EZH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,5475
Polymers46,1082
Non-polymers4393
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2900 Å2
ΔGint-19 kcal/mol
Surface area15090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)92.810, 177.909, 50.340
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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 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
#3: Chemical ChemComp-7W7 / (3R)-3-[(2H-1,3-benzodioxol-4-yl)methyl]piperidine-1-carboximidamide


Mass: 261.320 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H19N3O2
#4: Chemical ChemComp-YT3 / YTTRIUM (III) ION / Yttrium


Mass: 88.906 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Y
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1033 / 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: 2.25 Å3/Da / Density % sol: 45.42 %
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: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 0.92 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Feb 22, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 1.6→82.29 Å / Num. obs: 110710 / % possible obs: 97.2 % / Redundancy: 5.8 % / Biso Wilson estimate: 20.73 Å2 / Net I/σ(I): 8

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Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
XDSdata reduction
SCALAdata scaling
AMoREphasing
RefinementResolution: 1.6→64.22 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.941 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.079 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.087 / SU Rfree Blow DPI: 0.087 / SU Rfree Cruickshank DPI: 0.081
RfactorNum. reflection% reflectionSelection details
Rfree0.2 5503 4.97 %RANDOM
Rwork0.168 ---
obs0.17 110614 99.8 %-
Displacement parametersBiso mean: 28.38 Å2
Baniso -1Baniso -2Baniso -3
1--5.4252 Å20 Å20 Å2
2--3.2454 Å20 Å2
3---2.1798 Å2
Refine analyzeLuzzati coordinate error obs: 0.21 Å
Refinement stepCycle: 1 / Resolution: 1.6→64.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6064 0 40 1033 7137
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.016280HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.068513HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2202SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes160HARMONIC2
X-RAY DIFFRACTIONt_gen_planes910HARMONIC5
X-RAY DIFFRACTIONt_it6280HARMONIC20
X-RAY DIFFRACTIONt_nbd2SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion4.04
X-RAY DIFFRACTIONt_other_torsion15.3
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion808SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies12HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact8014SEMIHARMONIC4
LS refinement shellResolution: 1.6→1.64 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.248 397 4.98 %
Rwork0.225 7578 -
all0.226 7975 -
obs--98.9 %
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)
10.4855-0.1770.06811.7720.57731.38850.0168-0.014-0.0171-0.02870.079-0.0514-0.05160.0459-0.0958-0.07830.0072-0.0068-0.059-0.0084-0.063824.922465.61020.8571
20.3641-0.0256-0.14312.2620.92831.3367-0.0176-0.00260.0066-0.11550.1064-0.0775-0.05940.0591-0.0889-0.0708-0.01960.0213-0.0637-0.004-0.078327.45719.37324.0938
30.9962-1.3227-0.58262.02510.05591.8713-0.0428-0.1496-0.02390.31560.0370.20280.3303-0.05340.00580.0491-0.04480.0204-0.02420.0361-0.089617.199955.937713.788
42.24650.9095-0.52971.95140.62361.2057-0.0390.068-0.0204-0.6807-0.07320.2994-0.4436-0.16750.11220.1510.0274-0.0648-0.07760.0133-0.132117.27927.322511.7321
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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