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5ij7

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==Structure of Hs/AcPRC2 in complex with a pyridone inhibitor==
==Structure of Hs/AcPRC2 in complex with a pyridone inhibitor==
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<StructureSection load='5ij7' size='340' side='right' caption='[[5ij7]], [[Resolution|resolution]] 2.62&Aring;' scene=''>
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<StructureSection load='5ij7' size='340' side='right'caption='[[5ij7]], [[Resolution|resolution]] 2.62&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5ij7]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Anoca Anoca] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IJ7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IJ7 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5ij7]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Anolis_carolinensis Anolis carolinensis] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IJ7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5IJ7 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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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.62&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ij8|5ij8]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EZH2, KMT6 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=28377 ANOCA]), EED ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), SUZ12, CHET9, JJAZ1, KIAA0160 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5ij7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ij7 OCA], [https://pdbe.org/5ij7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ij7 RCSB], [https://www.ebi.ac.uk/pdbsum/5ij7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ij7 ProSAT]</span></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=5ij7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ij7 OCA], [http://pdbe.org/5ij7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ij7 RCSB], [http://www.ebi.ac.uk/pdbsum/5ij7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ij7 ProSAT]</span></td></tr>
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</table>
</table>
== Disease ==
== 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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[https://www.uniprot.org/uniprot/EZH2_HUMAN EZH2_HUMAN] Weaver syndrome. The disease is caused by mutations affecting the gene represented in this entry.
== Function ==
== 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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[https://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> [https://www.uniprot.org/uniprot/G1KPH4_ANOCA G1KPH4_ANOCA]
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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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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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==See Also==
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*[[Polycomb complex proteins 3D structures|Polycomb complex proteins 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 5ij7" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Anoca]]
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[[Category: Anolis carolinensis]]
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[[Category: Histone-lysine N-methyltransferase]]
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[[Category: Homo sapiens]]
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[[Category: Human]]
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[[Category: Large Structures]]
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[[Category: Brooun, A]]
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[[Category: Brooun A]]
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[[Category: Deng, Y L]]
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[[Category: Deng Y-L]]
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[[Category: Gajiwala, K S]]
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[[Category: Gajiwala KS]]
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[[Category: Liu, W]]
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[[Category: Liu W]]
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[[Category: Lysine methyltransferase]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

Structure of Hs/AcPRC2 in complex with a pyridone inhibitor

PDB ID 5ij7

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