5k0m
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==Targeting the PRC2 complex through a novel protein-protein interaction inhibitor of EED== | ==Targeting the PRC2 complex through a novel protein-protein interaction inhibitor of EED== | ||
| - | <StructureSection load='5k0m' size='340' side='right' caption='[[5k0m]], [[Resolution|resolution]] 1.83Å' scene=''> | + | <StructureSection load='5k0m' size='340' side='right'caption='[[5k0m]], [[Resolution|resolution]] 1.83Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[5k0m]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5K0M OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[5k0m]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5K0M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5K0M FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6PU:(3R,4S)-1-[(1S)-7-FLUORO-2,3-DIHYDRO-1H-INDEN-1-YL]-N,N-DIMETHYL-4-{4-[4-(METHYLSULFONYL)PIPERAZIN-1-YL]PHENYL}PYRROLIDIN-3-AMINE'>6PU</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.83Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6PU:(3R,4S)-1-[(1S)-7-FLUORO-2,3-DIHYDRO-1H-INDEN-1-YL]-N,N-DIMETHYL-4-{4-[4-(METHYLSULFONYL)PIPERAZIN-1-YL]PHENYL}PYRROLIDIN-3-AMINE'>6PU</scene></td></tr> |
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5k0m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k0m OCA], [https://pdbe.org/5k0m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5k0m RCSB], [https://www.ebi.ac.uk/pdbsum/5k0m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5k0m ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
| - | [ | + | [https://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 == | ||
| + | Polycomb repressive complex 2 (PRC2) is a regulator of epigenetic states required for development and homeostasis. PRC2 trimethylates histone H3 at lysine 27 (H3K27me3), which leads to gene silencing, and is dysregulated in many cancers. The embryonic ectoderm development (EED) protein is an essential subunit of PRC2 that has both a scaffolding function and an H3K27me3-binding function. Here we report the identification of A-395, a potent antagonist of the H3K27me3 binding functions of EED. Structural studies demonstrate that A-395 binds to EED in the H3K27me3-binding pocket, thereby preventing allosteric activation of the catalytic activity of PRC2. Phenotypic effects observed in vitro and in vivo are similar to those of known PRC2 enzymatic inhibitors; however, A-395 retains potent activity against cell lines resistant to the catalytic inhibitors. A-395 represents a first-in-class antagonist of PRC2 protein-protein interactions (PPI) for use as a chemical probe to investigate the roles of EED-containing protein complexes. | ||
| + | |||
| + | The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex.,He Y, Selvaraju S, Curtin ML, Jakob CG, Zhu H, Comess KM, Shaw B, The J, Lima-Fernandes E, Szewczyk MM, Cheng D, Klinge KL, Li HQ, Pliushchev M, Algire MA, Maag D, Guo J, Dietrich J, Panchal SC, Petros AM, Sweis RF, Torrent M, Bigelow LJ, Senisterra G, Li F, Kennedy S, Wu Q, Osterling DJ, Lindley DJ, Gao W, Galasinski S, Barsyte-Lovejoy D, Vedadi M, Buchanan FG, Arrowsmith CH, Chiang GG, Sun C, Pappano WN Nat Chem Biol. 2017 Apr;13(4):389-395. doi: 10.1038/nchembio.2306. Epub 2017 Jan , 30. PMID:28135237<ref>PMID:28135237</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 5k0m" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Polycomb complex proteins 3D structures|Polycomb complex proteins 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| - | [[Category: | + | [[Category: Homo sapiens]] |
| - | [[Category: | + | [[Category: Large Structures]] |
| - | [[Category: | + | [[Category: Bigelow LJ]] |
| - | [[Category: | + | [[Category: Jakob CG]] |
| - | [[Category: | + | [[Category: Sun C]] |
| - | [[Category: | + | [[Category: Zhu H]] |
Current revision
Targeting the PRC2 complex through a novel protein-protein interaction inhibitor of EED
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Categories: Homo sapiens | Large Structures | Bigelow LJ | Jakob CG | Sun C | Zhu H
