6w7f
From Proteopedia
(Difference between revisions)
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==Structure of EED bound to inhibitor 5285== | ==Structure of EED bound to inhibitor 5285== | ||
| - | <StructureSection load='6w7f' size='340' side='right'caption='[[6w7f]]' scene=''> | + | <StructureSection load='6w7f' size='340' side='right'caption='[[6w7f]], [[Resolution|resolution]] 2.20Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6W7F OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6W7F FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6w7f]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6W7F OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6W7F FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6w7f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w7f OCA], [http://pdbe.org/6w7f PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6w7f RCSB], [http://www.ebi.ac.uk/pdbsum/6w7f PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6w7f ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=Q3D:8-(6-cyclopropylpyridin-3-yl)-N-[(5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl]-1-(methylsulfonyl)imidazo[1,5-c]pyrimidin-5-amine'>Q3D</scene></td></tr> |
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EED ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6w7f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w7f OCA], [http://pdbe.org/6w7f PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6w7f RCSB], [http://www.ebi.ac.uk/pdbsum/6w7f PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6w7f ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/EED_HUMAN EED_HUMAN]] Polycomb group (PcG) protein. Component of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' and 'Lys-27' of histone H3, leading to transcriptional repression of the affected target gene. Also recognizes 'Lys-26' trimethylated histone H1 with the effect of inhibiting PRC2 complex methyltransferase activity on nucleosomal histone H3 'Lys-27', whereas H3 'Lys-27' recognition has the opposite effect, enabling the propagation of this repressive mark. The PRC2/EED-EZH2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems. Genes repressed by the PRC2/EED-EZH2 complex include HOXC8, HOXA9, MYT1 and CDKN2A.<ref>PMID:9584199</ref> <ref>PMID:10581039</ref> <ref>PMID:14532106</ref> <ref>PMID:15385962</ref> <ref>PMID:15231737</ref> <ref>PMID:15225548</ref> <ref>PMID:16357870</ref> <ref>PMID:18285464</ref> <ref>PMID:20974918</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Inhibition of embryonic ectoderm development (EED) is a new cancer therapeutic strategy. Herein, we report our discovery of EEDi-5285 as an exceptionally potent, efficacious, and orally active EED inhibitor. EEDi-5285 binds to the EED protein with an IC50 value of 0.2 nM and inhibits cell growth with IC50 values of 20 pM and 0.5 nM in the Pfeiffer and KARPAS422 lymphoma cell lines, respectively, carrying an EZH2 mutation. EEDi-5285 is approximately 100 times more potent than EED226 in binding to EED and >300 times more potent than EED226 in inhibition of cell growth in the KARPAS422 cell line. EEDi-5285 has excellent pharmacokinetics and achieves complete and durable tumor regression in the KARPAS422 xenograft model in mice with oral administration. The cocrystal structure of EEDi-5285 in a complex with EED defines the precise structural basis for their high binding affinity. EEDi-5285 is the most potent and efficacious EED inhibitor reported to date. | ||
| + | |||
| + | EEDi-5285: An Exceptionally Potent, Efficacious, and Orally Active Small-Molecule Inhibitor of Embryonic Ectoderm Development.,Rej RK, Wang C, Lu J, Wang M, Petrunak E, Zawacki KP, McEachern D, Fernandez-Salas E, Yang CY, Wang L, Li R, Chinnaswamy K, Wen B, Sun D, Stuckey J, Zhou Y, Chen J, Tang G, Wang S J Med Chem. 2020 Jun 24. doi: 10.1021/acs.jmedchem.0c00479. PMID:32580550<ref>PMID:32580550</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6w7f" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Petrunak | + | [[Category: Petrunak, E M]] |
| - | [[Category: Stuckey | + | [[Category: Stuckey, J A]] |
| + | [[Category: Gene regulation]] | ||
| + | [[Category: Inhibitor]] | ||
| + | [[Category: Transcription-inhibitor complex]] | ||
Revision as of 11:43, 22 July 2020
Structure of EED bound to inhibitor 5285
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