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- PDB-5wg6: Human Polycomb Repressive Complex 2 in complex with GSK126 inhibitor -

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Basic information

Entry
Database: PDB / ID: 5wg6
TitleHuman Polycomb Repressive Complex 2 in complex with GSK126 inhibitor
Components
  • Histone-lysine N-methyltransferase EZH2,Polycomb protein SUZ12 (E.C.2.1.1.43) chimera
  • Polycomb protein EED
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / complex / epigenetics / transferase / 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 / sex chromatin / negative regulation of keratinocyte differentiation / histone H3K27 trimethyltransferase activity / negative regulation of retinoic acid receptor signaling pathway ...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 / sex chromatin / negative regulation of keratinocyte differentiation / histone H3K27 trimethyltransferase activity / negative regulation of retinoic acid receptor signaling pathway / random inactivation of X chromosome / 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 / RSC-type 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 / oligodendrocyte differentiation / negative regulation of transcription elongation by RNA polymerase II / Transcriptional Regulation by E2F6 / subtelomeric heterochromatin formation / negative regulation of cell differentiation / 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 / methylated histone binding / SUMOylation of chromatin organization proteins / 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 / cell population proliferation / chromosome, telomeric region / nuclear body / ribonucleoprotein complex / 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 / nucleolus / regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / nucleoplasm / identical protein binding / metal ion binding / nucleus / cytosol
Similarity search - Function
EZH2, SET domain / Polycomb protein, VEFS-Box / VEFS-Box of polycomb protein / : / 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 ...EZH2, SET domain / Polycomb protein, VEFS-Box / VEFS-Box of polycomb protein / : / 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 / Zinc finger C2H2 type domain signature. / 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
Similarity search - Domain/homology
Chem-A9G / Polycomb protein EED / Polycomb protein SUZ12 / Histone-lysine N-methyltransferase EZH2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.901 Å
AuthorsBratkowski, M.A. / Liu, X.
Funding support United States, 6items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM114576 United States
Welch FoundationI-1790 United States
Rita Allen Foundation United States
Cancer Prevention and Research Institute of Texas (CPRIT)R1119 United States
UT Southwestern Endowed Scholar Fund United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM121662 United States
CitationJournal: Sci Rep / Year: 2018
Title: An Evolutionarily Conserved Structural Platform for PRC2 Inhibition by a Class of Ezh2 Inhibitors.
Authors: Bratkowski, M. / Yang, X. / Liu, X.
History
DepositionJul 13, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 27, 2018Provider: repository / Type: Initial release
Revision 1.1Apr 24, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Jan 8, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Mar 23, 2022Group: Author supporting evidence / Database references / Derived calculations
Category: database_2 / pdbx_audit_support / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Revision 1.4Oct 4, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Histone-lysine N-methyltransferase EZH2,Polycomb protein SUZ12 (E.C.2.1.1.43) chimera
B: Polycomb protein EED
C: Histone-lysine N-methyltransferase EZH2,Polycomb protein SUZ12 (E.C.2.1.1.43) chimera
D: Polycomb protein EED
hetero molecules


Theoretical massNumber of molelcules
Total (without water)300,59421
Polymers299,0214
Non-polymers1,57317
Water0
1
A: Histone-lysine N-methyltransferase EZH2,Polycomb protein SUZ12 (E.C.2.1.1.43) chimera
B: Polycomb protein EED
hetero molecules


Theoretical massNumber of molelcules
Total (without water)150,56011
Polymers149,5102
Non-polymers1,0509
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8370 Å2
ΔGint-99 kcal/mol
Surface area38980 Å2
MethodPISA
2
C: Histone-lysine N-methyltransferase EZH2,Polycomb protein SUZ12 (E.C.2.1.1.43) chimera
D: Polycomb protein EED
hetero molecules


Theoretical massNumber of molelcules
Total (without water)150,03410
Polymers149,5102
Non-polymers5238
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5420 Å2
ΔGint-80 kcal/mol
Surface area39680 Å2
MethodPISA
Unit cell
Length a, b, c (Å)243.880, 243.880, 243.699
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number97
Space group name H-MI422

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Components

#1: Protein Histone-lysine N-methyltransferase EZH2,Polycomb protein SUZ12 (E.C.2.1.1.43) chimera / ENX-1 / Enhancer of zeste homolog 2 / Lysine N-methyltransferase 6


Mass: 99155.523 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EZH2, KMT6, SUZ12, CHET9, JJAZ1, KIAA0160 / Production host: Saccharomyces cerevisiae (brewer's yeast)
References: UniProt: Q15910, UniProt: Q15022, histone-lysine N-methyltransferase
#2: Protein Polycomb protein EED / / hEED / Embryonic ectoderm development protein / WD protein associating with integrin cytoplasmic ...hEED / Embryonic ectoderm development protein / WD protein associating with integrin cytoplasmic tails 1 / WAIT-1


Mass: 50354.766 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EED / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: O75530
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-A9G / 1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indole-4-carboxamide


Mass: 526.672 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H38N6O2
Sequence detailsTHIS MUTATION INADVERTENTLY OCCURRED DURING CLONING.

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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: 3.03 Å3/Da / Density % sol: 59.4 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.2 / Details: 200 mM ammonium citrate pH 7.2, 16% PEG 3350

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Nov 10, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 3.9→50 Å / Num. obs: 33621 / % possible obs: 100 % / Redundancy: 26.2 % / CC1/2: 0.932 / Rmerge(I) obs: 0.375 / Rpim(I) all: 0.075 / Net I/σ(I): 14.6
Reflection shellResolution: 3.9→3.97 Å / Redundancy: 26.2 % / Rmerge(I) obs: 4.734 / Mean I/σ(I) obs: 1.17 / Num. unique obs: 1643 / CC1/2: 0.646 / Rpim(I) all: 0.939 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575)refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5IJ7

5ij7


Resolution: 3.901→40.647 Å / SU ML: 0.52 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.04 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3 1367 5.1 %
Rwork0.242 --
obs0.245 26797 79.66 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.901→40.647 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13419 0 55 0 13474
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00813821
X-RAY DIFFRACTIONf_angle_d0.75418557
X-RAY DIFFRACTIONf_dihedral_angle_d5.2898310
X-RAY DIFFRACTIONf_chiral_restr0.051965
X-RAY DIFFRACTIONf_plane_restr0.0052392
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.9013-4.04070.2984520.2639786X-RAY DIFFRACTION25
4.0407-4.20230.38780.24761192X-RAY DIFFRACTION38
4.2023-4.39330.2689950.2381707X-RAY DIFFRACTION54
4.3933-4.62470.3021350.24272519X-RAY DIFFRACTION80
4.6247-4.91390.28121510.23663125X-RAY DIFFRACTION98
4.9139-5.29260.28452020.24553122X-RAY DIFFRACTION100
5.2926-5.82380.31661720.25323163X-RAY DIFFRACTION100
5.8238-6.66340.34721490.2673216X-RAY DIFFRACTION100
6.6634-8.3830.37331580.24923261X-RAY DIFFRACTION100
8.383-40.64890.24961750.21673339X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: -68.3387 Å / Origin y: -22.3818 Å / Origin z: -37.2141 Å
111213212223313233
T0.1831 Å20.0389 Å2-0.4267 Å2-0.2862 Å2-1.0687 Å2---0.4854 Å2
L-0.1169 °20.1145 °20.108 °2-0.0743 °20.1946 °2--0.3604 °2
S0.0824 Å °-0.0931 Å °-0.3512 Å °0.1121 Å °0.1887 Å °-0.4116 Å °0.2265 Å °0.5964 Å °-0.2484 Å °
Refinement TLS groupSelection details: all

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