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- PDB-6b3w: Structure of Hs/AcPRC2 in complex with 5,8-dichloro-7-(3,5-dimeth... -

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Basic information

Entry
Database: PDB / ID: 6b3w
TitleStructure of Hs/AcPRC2 in complex with 5,8-dichloro-7-(3,5-dimethyl-1,2-oxazol-4-yl)-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3,4-dihydroisoquinolin-1(2H)-one
Components
  • Enhancer of zeste 2 polycomb repressive complex 2 subunit,Enhancer of zeste 2 polycomb repressive complex 2 subunit
  • Polycomb protein EED
  • Polycomb protein SUZ12
KeywordsMETAL BINDING PROTEIN / LYSINE METHYLTRANSFERASE
Function / homology
Function and homology information


[histone H3]-lysine27 N-trimethyltransferase / histone H3K27 trimethyltransferase activity / random inactivation of X chromosome / regulation of adaxial/abaxial pattern formation / sex chromatin / facultative heterochromatin formation / genomic imprinting / ESC/E(Z) complex / RSC-type complex / chromatin silencing complex ...[histone H3]-lysine27 N-trimethyltransferase / histone H3K27 trimethyltransferase activity / random inactivation of X chromosome / regulation of adaxial/abaxial pattern formation / sex chromatin / facultative heterochromatin formation / genomic imprinting / ESC/E(Z) complex / RSC-type complex / chromatin silencing complex / histone H3K9me2/3 reader activity / pronucleus / spinal cord development / lncRNA binding / Transcriptional Regulation by E2F6 / : / oligodendrocyte differentiation / negative regulation of cell differentiation / SUMOylation of chromatin organization proteins / cellular response to leukemia inhibitory factor / Regulation of PTEN gene transcription / transcription corepressor binding / PRC2 methylates histones and DNA / Defective pyroptosis / promoter-specific chromatin binding / enzyme activator activity / protein-DNA complex / chromatin DNA binding / PKMTs methylate histone lysines / Activation of anterior HOX genes in hindbrain development during early embryogenesis / HCMV Early Events / rhythmic process / heterochromatin formation / Oxidative Stress Induced Senescence / methylation / cell population proliferation / nuclear body / RNA polymerase II cis-regulatory region sequence-specific DNA binding / ribonucleoprotein complex / negative regulation of DNA-templated transcription / positive regulation of cell population proliferation / chromatin binding / nucleolus / negative regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm / metal ion binding / identical protein binding / nucleus / cytosol
Similarity search - Function
Polycomb protein SUZ12-like, Zn domain / EZH2, SET domain / Polycomb protein, VEFS-Box / VEFS-Box of polycomb protein / 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 ...Polycomb protein SUZ12-like, Zn domain / EZH2, SET domain / Polycomb protein, VEFS-Box / VEFS-Box of polycomb protein / 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 / Zinc finger C2H2 type domain signature. / 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-CJG / Histone-lysine N-methyltransferase EZH2 / Polycomb protein EED / Polycomb protein SUZ12
Similarity search - Component
Biological speciesAnolis carolinensis (green anole)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.05 Å
AuthorsGajiwala, K.S. / Brooun, A. / Liu, W. / Deng, Y. / Stewart, A.E.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7- ...Title: Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497).
Authors: Kung, P.P. / Bingham, P. / Brooun, A. / Collins, M. / Deng, Y.L. / Dinh, D. / Fan, C. / Gajiwala, K.S. / Grantner, R. / Gukasyan, H.J. / Hu, W. / Huang, B. / Kania, R. / Kephart, S.E. / ...Authors: Kung, P.P. / Bingham, P. / Brooun, A. / Collins, M. / Deng, Y.L. / Dinh, D. / Fan, C. / Gajiwala, K.S. / Grantner, R. / Gukasyan, H.J. / Hu, W. / Huang, B. / Kania, R. / Kephart, S.E. / Krivacic, C. / Kumpf, R.A. / Khamphavong, P. / Kraus, M. / Liu, W. / Maegley, K.A. / Nguyen, L. / Ren, S. / Richter, D. / Rollins, R.A. / Sach, N. / Sharma, S. / Sherrill, J. / Spangler, J. / Stewart, A.E. / Sutton, S. / Uryu, S. / Verhelle, D. / Wang, H. / Wang, S. / Wythes, M. / Xin, S. / Yamazaki, S. / Zhu, H. / Zhu, J. / Zehnder, L. / Edwards, M.
History
DepositionSep 25, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 27, 2017Provider: repository / Type: Initial release
Revision 1.1Feb 21, 2018Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation.year / _citation_author.name
Revision 1.2Oct 4, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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 1.3Nov 20, 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: Enhancer of zeste 2 polycomb repressive complex 2 subunit,Enhancer of zeste 2 polycomb repressive complex 2 subunit
B: Enhancer of zeste 2 polycomb repressive complex 2 subunit,Enhancer of zeste 2 polycomb repressive complex 2 subunit
E: Polycomb protein EED
F: Polycomb protein EED
S: Polycomb protein SUZ12
T: Polycomb protein SUZ12
hetero molecules


Theoretical massNumber of molelcules
Total (without water)275,78222
Polymers273,9746
Non-polymers1,80816
Water00
1
A: Enhancer of zeste 2 polycomb repressive complex 2 subunit,Enhancer of zeste 2 polycomb repressive complex 2 subunit
F: Polycomb protein EED
T: Polycomb protein SUZ12
hetero molecules


Theoretical massNumber of molelcules
Total (without water)137,89111
Polymers136,9873
Non-polymers9048
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area13830 Å2
ΔGint-78 kcal/mol
Surface area42510 Å2
MethodPISA
2
B: Enhancer of zeste 2 polycomb repressive complex 2 subunit,Enhancer of zeste 2 polycomb repressive complex 2 subunit
E: Polycomb protein EED
S: Polycomb protein SUZ12
hetero molecules


Theoretical massNumber of molelcules
Total (without water)137,89111
Polymers136,9873
Non-polymers9048
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area13660 Å2
ΔGint-77 kcal/mol
Surface area42650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.778, 115.178, 150.967
Angle α, β, γ (deg.)90.000, 102.580, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Enhancer of zeste 2 polycomb repressive complex 2 subunit,Enhancer of zeste 2 polycomb repressive complex 2 subunit


Mass: 72941.484 Da / Num. of mol.: 2 / Fragment: UNP RESIDUES 4-332, 420-478, 502-737
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Anolis carolinensis (green anole) / Gene: EZH2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: G1KPH4
#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: 41776.535 Da / Num. of mol.: 2 / Fragment: UNP residues 81-441
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EED / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O75530
#3: Protein Polycomb protein SUZ12 / Chromatin precipitated E2F target 9 protein / ChET 9 protein / Joined to JAZF1 protein / Suppressor ...Chromatin precipitated E2F target 9 protein / ChET 9 protein / Joined to JAZF1 protein / Suppressor of zeste 12 protein homolog


Mass: 22268.748 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SUZ12, CHET9, JJAZ1, KIAA0160 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q15022
#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-CJG / 5,8-dichloro-7-(3,5-dimethyl-1,2-oxazol-4-yl)-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3,4-dihydroisoquinolin-1(2H)-one


Mass: 446.326 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H21Cl2N3O3
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: 2.19 Å3/Da / Density % sol: 43.89 %
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop / pH: 6.2
Details: 23.0 %w/v PEG monomethyl ether 2000, 0.0050 M TCEP hydrochloride, 0.1 M MES (pH 6.20)

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Data collection

DiffractionMean temperature: 98 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Oct 19, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.05→147.34 Å / Num. obs: 45666 / % possible obs: 98.7 % / Redundancy: 3.4 % / Net I/σ(I): 12.6

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Processing

Software
NameVersionClassification
CNS2005refinement
Aimlessdata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5IJ7

5ij7


Resolution: 3.05→147.34 Å / Rfactor Rfree error: 0.006 / Data cutoff high absF: 1423251 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.282 2252 5.1 %RANDOM
Rwork0.224 ---
obs0.227 45205 98.4 %-
all-45205 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 43.967 Å2 / ksol: 0.3486 e/Å3
Displacement parametersBiso max: 125.23 Å2 / Biso mean: 65.9 Å2 / Biso min: 26.24 Å2
Baniso -1Baniso -2Baniso -3
1-6.97 Å20 Å2-0.95 Å2
2---12.54 Å20 Å2
3---5.58 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.47 Å0.37 Å
Luzzati d res low-5 Å
Luzzati sigma a0.58 Å0.48 Å
Refinement stepCycle: final / Resolution: 3.05→147.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15490 0 74 0 15564
Biso mean--50.12 --
Num. residues----1901
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg1.1
X-RAY DIFFRACTIONc_dihedral_angle_d24.3
X-RAY DIFFRACTIONc_improper_angle_d0.68
X-RAY DIFFRACTIONc_mcbond_it1.291.5
X-RAY DIFFRACTIONc_mcangle_it2.32
X-RAY DIFFRACTIONc_scbond_it1.582
X-RAY DIFFRACTIONc_scangle_it2.62.5
LS refinement shellResolution: 3.05→3.24 Å / Rfactor Rfree error: 0.02 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.395 394 5.4 %
Rwork0.349 6956 -
all-7350 -
obs--98.3 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2dna-rna_rep.paramdna-rna.top
X-RAY DIFFRACTION3water_rep.paramwater.top
X-RAY DIFFRACTION4ion.paramion.top
X-RAY DIFFRACTION5lig-edited.parlig-edited.top

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