5h24: Difference between revisions

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

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-'''Unreleased structure'''
-The entry 5h24 is ON HOLD
+==EED in complex with PRC2 allosteric inhibitor compound 8==
+<StructureSection load='5h24' size='340' side='right'caption='[[5h24]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5h24]] is a 4 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=5H24 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5H24 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LQG:5-(FURAN-2-YLMETHYLAMINO)-[1,2,4]TRIAZOLO[4,3-A]PYRIDINE-6-CARBONITRILE'>LQG</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=5h24 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5h24 OCA], [https://pdbe.org/5h24 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5h24 RCSB], [https://www.ebi.ac.uk/pdbsum/5h24 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5h24 ProSAT]</span></td></tr>
+</table>
+== 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 ==
+Overexpression and somatic heterozygous mutations of EZH2, the catalytic subunit Polycomb repressive complex 2 (PRC2), are associated with several tumor types. EZH2 inhibitor, EPZ-6438 (Tazemetostat), demonstrated clinical efficacy in patients with acceptable safety profile as monotherapy. EED, another subunit of PRC2 complex, is essential for its histone methyltransferase activity through direct binding to trimethylated lysine 27 on histone 3 (H3K27Me3). Herein we disclose the discovery of a first-in-class potent, selective and orally bioavailable EED inhibitor EED226 (compound 43). Guided by X-ray crystallography, compound 43 discovered by fragmentation and regrowth of Compound 7, a PRC2 HTS hit that directly binds EED. Scaffold hopping followed by ensuing multi-parameter optimization led to the discovery compound 43. Compound 43 induces robust and sustained tumor regression in EZH2MUT pre-clinical DLBCL model. For the first time we demonstrate that specific and direct inhibition of EED can be effective as an anti-cancer strategy.
-Authors: Zhao, K., Zhao, M., Luo, X., Zhang, H.
+Discovery of First-in-Class, Potent and Orally Bioavailable EED inhibitor with Robust Anti-cancer Efficacy.,Huang Y, Zhang J, Yu Z, Zhang H, Wang Y, Lingel A, Qi W, Gu XJ, Zhao K, Shultz MD, Wang L, Fu X, Sun Y, Zhang Q, Jiang X, Zhang JW, Zhang C, Li L, Zeng J, Feng L, Zhang C, Liu Y, Zhang M, Zhang L, Zhao M, Gao Z, Liu X, Fang D, Guo H, Mi Y, Gabriel T, Dillon MP, Atadja P, Oyang C J Med Chem. 2017 Jan 16. doi: 10.1021/acs.jmedchem.6b01576. PMID:28092155<ref>PMID:28092155</ref>
-Description: EED in complex with an allosteric PRC2 inhibitor
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Zhang, H]]
+<div class="pdbe-citations 5h24" style="background-color:#fffaf0;"></div>
-[[Category: Zhao, M]]
-[[Category: Luo, X]]
+==See Also==
-[[Category: Zhao, K]]
+*[[Polycomb complex proteins 3D structures|Polycomb complex proteins 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Luo X]]
+[[Category: Zhang H]]
+[[Category: Zhao K]]
+[[Category: Zhao M]]