5ylt
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of SET7/9 in complex with a cyproheptadine derivative== | |
| + | <StructureSection load='5ylt' size='340' side='right' caption='[[5ylt]], [[Resolution|resolution]] 1.69Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5ylt]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5YLT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5YLT FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C7N:2-(1-methylpiperidin-4-ylidene)tricyclo[9.4.0.0^{3,8}]pentadeca-1(11),3(8),4,6,9,12,14-heptaen-6-ol'>C7N</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SFG:SINEFUNGIN'>SFG</scene></td></tr> | ||
| + | <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> | ||
| + | <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=5ylt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ylt OCA], [http://pdbe.org/5ylt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ylt RCSB], [http://www.ebi.ac.uk/pdbsum/5ylt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ylt ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/SETD7_HUMAN SETD7_HUMAN]] Histone methyltransferase that specifically monomethylates 'Lys-4' of histone H3. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. Plays a central role in the transcriptional activation of genes such as collagenase or insulin. Recruited by IPF1/PDX-1 to the insulin promoter, leading to activate transcription. Has also methyltransferase activity toward non-histone proteins such as p53/TP53, TAF10, and possibly TAF7 by recognizing and binding the [KR]-[STA]-K in substrate proteins. Monomethylates 'Lys-189' of TAF10, leading to increase the affinity of TAF10 for RNA polymerase II. Monomethylates 'Lys-372' of p53/TP53, stabilizing p53/TP53 and increasing p53/TP53-mediated transcriptional activation.<ref>PMID:12588998</ref> <ref>PMID:15099517</ref> <ref>PMID:16141209</ref> <ref>PMID:17108971</ref> <ref>PMID:12540855</ref> <ref>PMID:15525938</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The histone methyltransferase SET7/9 methylates not only histone but also non-histone proteins as substrates, and therefore SET7/9 inhibitors are considered candidates for treatment of diseases. Previously, our group identified cyproheptadine, which is used clinically as a serotonin receptor antagonist or histamine receptor (H1) antagonist, as a novel scaffold of SET7/9 inhibitor. In this work, we focused on dibenzosuberene as a substructure of cyproheptadine, and synthesized derivatives with various functional groups. Among them, compound bearing a 2-hydroxy group showed the most potent activity. On the other hand, a 3-hydroxy group or other hydrophilic functional groups such as acetamide decreased the activity. Structural analysis clarified a rationale for the improved potency only by tightly restricted location and type of hydrophilic group. In addition, a SET7/9 loop, which was only partially visible in the complex with cyproheptadine, became more clearly visible in that with 2-hydroxycyproheptadine. These results are expected to be helpful for further structure-based development of SET7/9 inhibitors. | ||
| - | + | Development of novel inhibitors for histone methyltransferase SET7/9 based on cyproheptadine.,Hirano T, Fujiwara T, Niwa H, Hirano M, Ohira K, Okazaki Y, Sato S, Umehara T, Maemoto Y, Ito A, Yoshida M, Kagechika H ChemMedChem. 2018 Jun 7. doi: 10.1002/cmdc.201800233. PMID:29882380<ref>PMID:29882380</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 5ylt" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Histone-lysine N-methyltransferase]] | ||
| + | [[Category: Fujiwara, T]] | ||
| + | [[Category: Hirano, M]] | ||
| + | [[Category: Hirano, T]] | ||
| + | [[Category: Ito, A]] | ||
| + | [[Category: Kagechika, H]] | ||
| + | [[Category: Maemoto, Y]] | ||
| + | [[Category: Niwa, H]] | ||
| + | [[Category: Ohira, K]] | ||
| + | [[Category: Okazaki, Y]] | ||
| + | [[Category: Sato, S]] | ||
| + | [[Category: Umehara, T]] | ||
| + | [[Category: Yoshida, M]] | ||
| + | [[Category: Inhibitor]] | ||
| + | [[Category: Methyltransferase]] | ||
| + | [[Category: Set domain]] | ||
| + | [[Category: Transferase]] | ||
| + | [[Category: Transferase-transferase inhibitor complex]] | ||
Revision as of 05:43, 20 June 2018
Crystal structure of SET7/9 in complex with a cyproheptadine derivative
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