5u6d: Difference between revisions

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-'''Unreleased structure'''
-The entry 5u6d is ON HOLD  until Paper Publication
+==Polycomb protein EED in complex with inhibitor: 2-[4-(4-{(3S,4R)-4-(dimethylamino)-1-[(2-fluoro-6-methylphenyl)methyl]pyrrolidin-3-yl}phenyl)-1H-pyrazol-1-yl]acetamide==
+<StructureSection load='5u6d' size='340' side='right' caption='[[5u6d]], [[Resolution|resolution]] 1.64&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5u6d]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5U6D OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5U6D FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7XG:2-[4-(4-{(3S,4R)-4-(DIMETHYLAMINO)-1-[(2-FLUORO-6-METHYLPHENYL)METHYL]PYRROLIDIN-3-YL}PHENYL)-1H-PYRAZOL-1-YL]ACETAMIDE'>7XG</scene></td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5u69|5u69]]</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5u6d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u6d OCA], [http://pdbe.org/5u6d PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5u6d RCSB], [http://www.ebi.ac.uk/pdbsum/5u6d PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5u6d ProSAT]</span></td></tr>
+</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 ==
+Herein we disclose SAR studies of a series of dimethylamino pyrrolidines which we recently reported as novel inhibitors of the PRC2 complex through disruption of EED/H3K27me3 binding. Modification of the indole and benzyl moieties of screening hit 1 provided analogs with substantially improved binding and cellular activities. This work culminated in the identification of compound 2, our nanomolar proof-of-concept (PoC) inhibitor which provided on-target tumor growth inhibition in a mouse xenograft model. X-ray crystal structures of several inhibitors bound in the EED active-site are also discussed.
-Authors:
+SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding.,Curtin ML, Pliushchev MA, Li HQ, Torrent M, Dietrich JD, Jakob CG, Zhu H, Zhao H, Wang Y, Ji Z, Clark RF, Sarris KA, Selvaraju S, Shaw B, Algire MA, He Y, Richardson PL, Sweis RF, Sun C, Chiang GG, Michaelides MR Bioorg Med Chem Lett. 2017 Apr 1;27(7):1576-1583. doi:, 10.1016/j.bmcl.2017.02.030. Epub 2017 Feb 20. PMID:28254486<ref>PMID:28254486</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 5u6d" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Jakob, C G]]
+[[Category: Zhu, H]]
+[[Category: Inhibitor]]
+[[Category: Protein binding]]
+[[Category: Wd40 prc2]]