5ylt
Crystal structure of SET7/9 in complex with a cyproheptadine derivative
Structural highlights
FunctionSETD7_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.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedThe 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[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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