5ij8

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'''Unreleased structure'''
 
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The entry 5ij8 is ON HOLD
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==Structure of the primary oncogenic mutant Y641N Hs/AcPRC2 in complex with a pyridone inhibitor==
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<StructureSection load='5ij8' size='340' side='right' caption='[[5ij8]], [[Resolution|resolution]] 2.99&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[5ij8]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IJ8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IJ8 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=6BN:5,8-DICHLORO-2-[(4-ETHYL-6-METHYL-2-OXO-1,2-DIHYDROPYRIDIN-3-YL)METHYL]-7-({1-[(2R)-2-HYDROXYPROPANOYL]PIPERIDIN-4-YL}OXY)-3,4-DIHYDROISOQUINOLIN-1(2H)-ONE'>6BN</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ij7|5ij7]]</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=5ij8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ij8 OCA], [http://pdbe.org/5ij8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ij8 RCSB], [http://www.ebi.ac.uk/pdbsum/5ij8 PDBsum]</span></td></tr>
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</table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/SUZ12_HUMAN SUZ12_HUMAN]] A chromosomal aberration involving SUZ12 may be a cause of endometrial stromal tumors. Translocation t(7;17)(p15;q21) with JAZF1. The translocation generates the JAZF1-SUZ12 oncogene consisting of the N-terminus part of JAZF1 and the C-terminus part of SUZ12. It is frequently found in all cases of endometrial stromal tumors, except in endometrial stromal sarcomas, where it is rarer.<ref>PMID:11371647</ref>
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== Function ==
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[[http://www.uniprot.org/uniprot/SUZ12_HUMAN SUZ12_HUMAN]] Polycomb group (PcG) protein. Component 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. 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:15225548</ref> <ref>PMID:15231737</ref> <ref>PMID:15385962</ref> <ref>PMID:16618801</ref> <ref>PMID:17344414</ref> <ref>PMID:18285464</ref> [[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Polycomb repressive complex 2 (PRC2) mediates gene silencing through chromatin reorganization by methylation of histone H3 lysine 27 (H3K27). Overexpression of the complex and point mutations in the individual subunits of PRC2 have been shown to contribute to tumorigenesis. Several inhibitors of the PRC2 activity have shown efficacy in EZH2-mutated lymphomas and are currently in clinical development, although the molecular basis of inhibitor recognition remains unknown. Here we report the crystal structures of the inhibitor-bound wild-type and Y641N PRC2. The structures illuminate an important role played by a stretch of 17 residues in the N-terminal region of EZH2, we call the activation loop, in the stimulation of the enzyme activity, inhibitor recognition and the potential development of the mutation-mediated drug resistance. The work presented here provides new avenues for the design and development of next-generation PRC2 inhibitors through establishment of a structure-based drug design platform.
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Authors: Gajiwala, K.S., Brooun, A.
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Polycomb repressive complex 2 structure with inhibitor reveals a mechanism of activation and drug resistance.,Brooun A, Gajiwala KS, Deng YL, Liu W, Bolanos B, Bingham P, He YA, Diehl W, Grable N, Kung PP, Sutton S, Maegley KA, Yu X, Stewart AE Nat Commun. 2016 Apr 28;7:11384. doi: 10.1038/ncomms11384. PMID:27122193<ref>PMID:27122193</ref>
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Description: Structure of the primary oncogenic mutant Y641N Hs/AcPRC2 in complex with a pyridone inhibitor
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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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[[Category: Gajiwala, K.S]]
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<div class="pdbe-citations 5ij8" 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]]
[[Category: Brooun, A]]
[[Category: Brooun, A]]
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[[Category: Deng, Y L]]
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[[Category: Gajiwala, K S]]
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[[Category: Liu, W]]
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[[Category: Lysine methyltransferase]]
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[[Category: Transferase-transferase inhibitor complex]]

Revision as of 05:13, 11 May 2016

Structure of the primary oncogenic mutant Y641N Hs/AcPRC2 in complex with a pyridone inhibitor

5ij8, resolution 2.99Å

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