5h24

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'''Unreleased structure'''
 
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The entry 5h24 is ON HOLD until Paper Publication
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==EED in complex with PRC2 allosteric inhibitor compound 8==
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<StructureSection load='5h24' size='340' side='right' caption='[[5h24]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[5h24]] is a 4 chain structure. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5H24 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=LQG:5-(FURAN-2-YLMETHYLAMINO)-[1,2,4]TRIAZOLO[4,3-A]PYRIDINE-6-CARBONITRILE'>LQG</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5h13|5h13]], [[5h14|5h14]], [[5h15|5h15]], [[5h17|5h17]], [[5h19|5h19]], [[5h25|5h25]]</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone-lysine_N-methyltransferase Histone-lysine N-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.43 2.1.1.43] </span></td></tr>
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<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=5h24 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5h24 OCA], [http://pdbe.org/5h24 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5h24 RCSB], [http://www.ebi.ac.uk/pdbsum/5h24 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5h24 ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/EZH2_HUMAN EZH2_HUMAN]] Weaver syndrome. The disease is caused by mutations affecting the gene represented in this entry.
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== Function ==
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[[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> [[http://www.uniprot.org/uniprot/EZH2_HUMAN EZH2_HUMAN]] Polycomb group (PcG) protein. Catalytic subunit of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' (H3K9me) and 'Lys-27' (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene. Able to mono-, di- and trimethylate 'Lys-27' of histone H3 to form H3K27me1, H3K27me2 and H3K27me3, respectively. Compared to EZH2-containing complexes, it is more abundant in embryonic stem cells and plays a major role in forming H3K27me3, which is required for embryonic stem cell identity and proper differentiation. 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, CDKN2A and retinoic acid target genes. EZH2 can also methylate non-histone proteins such as the transcription factor GATA4 and the nuclear receptor RORA.<ref>PMID:14532106</ref> <ref>PMID:15385962</ref> <ref>PMID:15231737</ref> <ref>PMID:15225548</ref> <ref>PMID:16179254</ref> <ref>PMID:16618801</ref> <ref>PMID:16357870</ref> <ref>PMID:16936726</ref> <ref>PMID:17210787</ref> <ref>PMID:17344414</ref> <ref>PMID:19026781</ref> <ref>PMID:18285464</ref> <ref>PMID:20935635</ref> <ref>PMID:23063525</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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Authors:
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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>
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Description:
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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<div class="pdbe-citations 5h24" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Histone-lysine N-methyltransferase]]
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[[Category: Luo, X]]
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[[Category: Zhang, H]]
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[[Category: Zhao, K]]
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[[Category: Zhao, M]]
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[[Category: Eed]]
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[[Category: Inhibitor]]
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[[Category: Prc2]]
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[[Category: Transferase-transferase inhibitor complex]]

Revision as of 23:32, 25 January 2017

EED in complex with PRC2 allosteric inhibitor compound 8

5h24, resolution 2.50Å

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