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- PDB-4w2r: Structure of Hs/AcPRC2 in complex with 5,8-dichloro-2-[(4-methoxy... -

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Basic information

Entry
Database: PDB / ID: 4w2r
TitleStructure of Hs/AcPRC2 in complex with 5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-[(R)-methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1(2H)-one
Components
  • Enhancer of zeste 2 polycomb repressive complex 2 subunit
  • Polycomb protein EED
  • Polycomb protein SUZ12
KeywordsTransferase/Transferase Inhibitor / LYSINE METHYLTRANSFERASE / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


[histone H3]-lysine27 N-trimethyltransferase / sex chromatin / histone H3K27 trimethyltransferase activity / random inactivation of X chromosome / facultative heterochromatin formation / ESC/E(Z) complex / chromatin silencing complex / RSC-type complex / lncRNA binding / spinal cord development ...[histone H3]-lysine27 N-trimethyltransferase / sex chromatin / histone H3K27 trimethyltransferase activity / random inactivation of X chromosome / facultative heterochromatin formation / ESC/E(Z) complex / chromatin silencing complex / RSC-type complex / lncRNA binding / spinal cord development / histone methyltransferase activity / Transcriptional Regulation by E2F6 / oligodendrocyte differentiation / negative regulation of cell differentiation / enzyme activator activity / methylated histone binding / SUMOylation of chromatin organization proteins / transcription corepressor binding / PRC2 methylates histones and DNA / Regulation of PTEN gene transcription / Defective pyroptosis / promoter-specific chromatin binding / chromatin DNA binding / heterochromatin formation / PKMTs methylate histone lysines / Activation of anterior HOX genes in hindbrain development during early embryogenesis / HCMV Early Events / rhythmic process / chromosome / Oxidative Stress Induced Senescence / methylation / cell population proliferation / nuclear body / ribonucleoprotein complex / RNA polymerase II cis-regulatory region sequence-specific DNA binding / negative regulation of DNA-templated transcription / chromatin binding / positive regulation of cell population proliferation / nucleolus / negative regulation of transcription by RNA polymerase II / nucleoplasm / identical protein binding / nucleus / metal ion binding / cytosol
Similarity search - Function
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, 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 / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / Zinc finger C2H2 type domain signature. / 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-CJD / 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: 2.81 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 1.2Sep 27, 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Enhancer of zeste 2 polycomb repressive complex 2 subunit
B: 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)275,82422
Polymers273,9746
Non-polymers1,85016
Water00
1
A: 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)137,91211
Polymers136,9873
Non-polymers9258
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area13900 Å2
ΔGint-79 kcal/mol
Surface area42440 Å2
MethodPISA
2
B: 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)137,91211
Polymers136,9873
Non-polymers9258
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area13740 Å2
ΔGint-80 kcal/mol
Surface area42600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.720, 115.484, 151.538
Angle α, β, γ (deg.)90.000, 102.400, 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


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-CJD / 5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-[(R)-methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1(2H)-one


Mass: 467.342 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H24Cl2N2O5

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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: 2.21 Å3/Da / Density % sol: 44.24 %
Crystal growTemperature: 286 K / Method: vapor diffusion, sitting drop / pH: 6.7
Details: Precipitant: 26.0 %w/v PEG monomethyl ether 2000, 0.0050 M TCEP hydrochloride, 0.1 M Bis_tris (pH 6.70)

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Data collection

DiffractionMean temperature: 98 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Mar 4, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.81→148.01 Å / Num. obs: 58162 / % possible obs: 99.8 % / Redundancy: 6.6 % / Biso Wilson estimate: 68.9 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.077 / Net I/σ(I): 20.9
Reflection shellResolution: 2.81→3.14 Å / Redundancy: 6.6 % / Rmerge(I) obs: 0.587 / Mean I/σ(I) obs: 3.2 / Num. unique all: 16475 / CC1/2: 0.907 / Rpim(I) all: 0.246 / % possible all: 100

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Processing

Software
NameClassification
CNSrefinement
Aimlessdata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5IJ7

5ij7


Resolution: 2.81→148.01 Å / Rfactor Rfree error: 0.005 / Data cutoff high absF: 1424624 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.266 2938 5.1 %RANDOM
Rwork0.218 ---
obs0.22 57937 99.8 %-
all-57937 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 48.0754 Å2 / ksol: 0.3516 e/Å3
Displacement parametersBiso max: 125.15 Å2 / Biso mean: 72.4 Å2 / Biso min: 35.29 Å2
Baniso -1Baniso -2Baniso -3
1-13.41 Å20 Å21.24 Å2
2---17.39 Å20 Å2
3---3.98 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.43 Å0.35 Å
Luzzati d res low-5 Å
Luzzati sigma a0.55 Å0.46 Å
Refinement stepCycle: final / Resolution: 2.81→148.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15494 0 76 0 15570
Biso mean--56.95 --
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_d23.5
X-RAY DIFFRACTIONc_improper_angle_d0.67
X-RAY DIFFRACTIONc_mcbond_it1.321.5
X-RAY DIFFRACTIONc_mcangle_it2.322
X-RAY DIFFRACTIONc_scbond_it1.742
X-RAY DIFFRACTIONc_scangle_it2.772.5
LS refinement shellResolution: 2.81→2.99 Å / Rfactor Rfree error: 0.016 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.355 486 5.1 %
Rwork0.323 9071 -
all-9557 -
obs--99.9 %
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.paramlig.top

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