View source for 5ylt


==Crystal structure of SET7/9 in complex with a cyproheptadine derivative==
<StructureSection load='5ylt' size='340' side='right'caption='[[5ylt]], [[Resolution|resolution]] 1.69&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5ylt]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. 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 [https://proteopedia.org/fgij/fg.htm?mol=5YLT FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.69&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5ylt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ylt OCA], [https://pdbe.org/5ylt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ylt RCSB], [https://www.ebi.ac.uk/pdbsum/5ylt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ylt ProSAT]</span></td></tr>
</table>
== Function ==
[https://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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5ylt" style="background-color:#fffaf0;"></div>

==See Also==
*[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[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]]