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- PDB-7msd: Structure of EED bound to EEDi-6068 -

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Basic information

Entry
Database: PDB / ID: 7msd
TitleStructure of EED bound to EEDi-6068
ComponentsPolycomb protein EED
KeywordsGENE REGULATION/INHIBITOR / polycomb repressive complex 2 / GENE REGULATION-INHIBITOR complex
Function / homology
Function and homology information


ESC/E(Z) complex / spinal cord development / histone methyltransferase activity / Transcriptional Regulation by E2F6 / enzyme activator activity / transcription corepressor binding / PRC2 methylates histones and DNA / Regulation of PTEN gene transcription / Defective pyroptosis / PKMTs methylate histone lysines ...ESC/E(Z) complex / spinal cord development / histone methyltransferase activity / Transcriptional Regulation by E2F6 / enzyme activator activity / transcription corepressor binding / PRC2 methylates histones and DNA / Regulation of PTEN gene transcription / Defective pyroptosis / PKMTs methylate histone lysines / Activation of anterior HOX genes in hindbrain development during early embryogenesis / HCMV Early Events / chromosome / Oxidative Stress Induced Senescence / negative regulation of DNA-templated transcription / chromatin binding / negative regulation of transcription by RNA polymerase II / nucleoplasm / identical protein binding / nucleus / cytosol
Similarity search - Function
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
FORMIC ACID / Chem-ZMY / Polycomb protein EED
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsPetrunak, E. / Stuckey, J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)P30 CA046592 United States
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery of EEDi-5273 as an Exceptionally Potent and Orally Efficacious EED Inhibitor Capable of Achieving Complete and Persistent Tumor Regression.
Authors: Rej, R.K. / Wang, C. / Lu, J. / Wang, M. / Petrunak, E. / Zawacki, K.P. / McEachern, D. / Yang, C.Y. / Wang, L. / Li, R. / Chinnaswamy, K. / Wen, B. / Sun, D. / Stuckey, J.A. / Zhou, Y. / ...Authors: Rej, R.K. / Wang, C. / Lu, J. / Wang, M. / Petrunak, E. / Zawacki, K.P. / McEachern, D. / Yang, C.Y. / Wang, L. / Li, R. / Chinnaswamy, K. / Wen, B. / Sun, D. / Stuckey, J.A. / Zhou, Y. / Chen, J. / Tang, G. / Wang, S.
History
DepositionMay 11, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 20, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 27, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Apr 3, 2024Group: 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: Polycomb protein EED
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,0213
Polymers42,4121
Non-polymers6082
Water3,837213
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)57.800, 85.570, 91.916
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: 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: 42412.180 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EED / Production host: Escherichia coli (E. coli) / References: UniProt: O75530
#2: Chemical ChemComp-ZMY / (9aP,12aR)-4-(2,2-difluoropropyl)-12-{[(5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl]amino}-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one


Mass: 562.466 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H20F6N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-FMT / FORMIC ACID / Formic acid


Mass: 46.025 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: CH2O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 213 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.68 Å3/Da / Density % sol: 54.1 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 0.1 M Tris pH 8.5, 20% glycerol, 4.5 M Na Formate, 10 mM TCEP

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.979 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Feb 11, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. obs: 23519 / % possible obs: 100 % / Redundancy: 7.3 % / Biso Wilson estimate: 36.74 Å2 / Rmerge(I) obs: 0.095 / Rpim(I) all: 0.038 / Rrim(I) all: 0.103 / Χ2: 0.933 / Net I/σ(I): 7.2 / Num. measured all: 172046
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.2-2.247.40.89711230.7740.3540.9650.99100
2.24-2.287.40.87411530.8010.3450.941.031100
2.28-2.327.40.77811620.8370.3060.8360.909100
2.32-2.377.40.62211520.8820.2450.6690.937100
2.37-2.427.40.59611510.8790.2340.6410.927100
2.42-2.487.40.52611620.8940.2070.5660.928100
2.48-2.547.40.42611610.9310.1670.4580.959100
2.54-2.617.40.37911640.9440.1490.4080.929100
2.61-2.697.40.31511610.960.1240.3390.964100
2.69-2.777.40.2711630.9720.1070.290.967100
2.77-2.877.40.21611750.9810.0840.2320.97100
2.87-2.997.40.17211670.9850.0680.1850.964100
2.99-3.127.40.12711700.9920.050.1370.994100
3.12-3.297.40.09111690.9950.0360.0971.041100
3.29-3.497.40.06711740.9960.0260.0721.018100
3.49-3.767.30.05311860.9970.0210.0570.971100
3.76-4.147.20.03912050.9980.0160.0420.861100
4.14-4.747.10.02911960.9990.0120.0320.793100
4.74-5.977.10.02912210.9990.0120.0310.699100
5.97-506.50.03113040.9980.0130.0340.79899.8

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Processing

Software
NameVersionClassification
BUSTER2.10.3 (6-FEB-2020)refinement
HKL-2000data reduction
HKL-2000data scaling
PDB_EXTRACT3.27data extraction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: in-house model

Resolution: 2.2→47.9 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.931 / SU R Cruickshank DPI: 0.208 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.223 / SU Rfree Blow DPI: 0.175 / SU Rfree Cruickshank DPI: 0.171
RfactorNum. reflection% reflectionSelection details
Rfree0.2125 1232 5.26 %RANDOM
Rwork0.1767 ---
obs0.1786 23444 98.5 %-
Displacement parametersBiso max: 76.66 Å2 / Biso mean: 33.09 Å2 / Biso min: 16.03 Å2
Baniso -1Baniso -2Baniso -3
1-1.7073 Å20 Å20 Å2
2---0.6715 Å20 Å2
3----1.0358 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: final / Resolution: 2.2→47.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2848 0 65 213 3126
Biso mean--38.28 46.01 -
Num. residues----359
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1014SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes551HARMONIC5
X-RAY DIFFRACTIONt_it2982HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion384SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2480SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3004HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg4112HARMONIC21.01
X-RAY DIFFRACTIONt_omega_torsion3.71
X-RAY DIFFRACTIONt_other_torsion16.25
LS refinement shellResolution: 2.2→2.23 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.2228 24 5.12 %
Rwork0.1977 445 -
all0.199 469 -
obs--58 %

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