5ylt: Difference between revisions
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==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 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]] 1.69Å</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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </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]] | |||
