5u5h
From Proteopedia
(Difference between revisions)
m (Protected "5u5h" [edit=sysop:move=sysop]) |
|||
| Line 1: | Line 1: | ||
| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of EED in complex with 6-(2-fluoro-5-methoxybenzyl)-1-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-3-amine 6-(2-fluoro-5-methoxybenzyl)-1-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-3-amine== | |
| + | <StructureSection load='5u5h' size='340' side='right' caption='[[5u5h]], [[Resolution|resolution]] 1.80Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5u5h]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5U5H OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5U5H FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7VV:(6S)-6-[(2-FLUORO-5-METHOXYPHENYL)METHYL]-1-(PROPAN-2-YL)-5,6,7,8-TETRAHYDROIMIDAZO[1,5-A]PYRIDIN-3-AMINE'>7VV</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5u5k|5u5k]], [[5u62|5u62]], [[5u5t|5u5t]]</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=5u5h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u5h OCA], [http://pdbe.org/5u5h PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5u5h RCSB], [http://www.ebi.ac.uk/pdbsum/5u5h PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5u5h 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 == | ||
| + | PRC2 is a multisubunit methyltransferase involved in epigenetic regulation of early embryonic development and cell growth. The catalytic subunit EZH2 methylates primarily lysine 27 of histone H3, leading to chromatin compaction and repression of tumor suppressor genes. Inhibiting this activity by small molecules targeting EZH2 was shown to result in antitumor efficacy. Here, we describe the optimization of a chemical series representing a new class of PRC2 inhibitors which acts allosterically via the trimethyllysine pocket of the noncatalytic EED subunit. Deconstruction of a larger and complex screening hit to a simple fragment-sized molecule followed by structure-guided regrowth and careful property modulation were employed to yield compounds which achieve submicromolar inhibition in functional assays and cellular activity. The resulting molecules can serve as a simplified entry point for lead optimization and can be utilized to study this new mechanism of PRC2 inhibition and the associated biology in detail. | ||
| - | + | Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Polycomb Repressive Complex 2 (PRC2) Methyltransferase.,Lingel A, Sendzik M, Huang Y, Shultz MD, Cantwell J, Dillon MP, Fu X, Fuller J, Gabriel T, Gu J, Jiang X, Li L, Liang F, McKenna M, Qi W, Rao W, Sheng X, Shu W, Sutton J, Taft B, Wang L, Zeng J, Zhang H, Zhang M, Zhao K, Lindvall M, Bussiere DE J Med Chem. 2017 Jan 12;60(1):415-427. doi: 10.1021/acs.jmedchem.6b01473. Epub, 2017 Jan 3. PMID:27992714<ref>PMID:27992714</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| + | <div class="pdbe-citations 5u5h" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
[[Category: Bussiere, D]] | [[Category: Bussiere, D]] | ||
[[Category: Shu, W]] | [[Category: Shu, W]] | ||
| + | [[Category: Eed]] | ||
| + | [[Category: Fragment-based generation]] | ||
| + | [[Category: Oncology]] | ||
| + | [[Category: Transcription]] | ||
Revision as of 07:38, 18 January 2017
Crystal structure of EED in complex with 6-(2-fluoro-5-methoxybenzyl)-1-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-3-amine 6-(2-fluoro-5-methoxybenzyl)-1-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-3-amine
| |||||||||||
