2015 Fiscal Year Final Research Report
Mechanistic Study of Allosteric Inhibition of PPARgamma Serine Phosphorylation
| Project/Area Number |
25860090
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Drug development chemistry
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| Research Institution | Showa Pharmaceutical University |
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Principal Investigator |
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| Project Period (FY) |
2013-04-01 – 2016-03-31
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| Keywords | PPARgamma / 構造生物学 / メディシナルケミストリー / 高度不飽和脂肪酸 |
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| Outline of Final Research Achievements |
To understand how PPARgamma ligands inhibit Ser245 phosphorylation, we have done several experiments. 1H-15N HSQC NMR experiment showed that some residues were significantly shifted by PPARgamma ligand. A signaling pathway from ligand to the shifted residues was revealed by using PPARgamma mutants. This is supported by circular dichroism spectroscopic experiments. To integrate our results, we used modeling software Sybyl-X and we proposed the main signaling pathway and mechanism of inhibition of Ser245 phspholylation by ligand.
Based on the mechanism, we planed to design and synthesis of partial agonist for PPARgamma. We established facile synthesis of 17-(S)HDHA then synthesized 17-oxoDHA, which showed PPARgamma partial agonistic activity, as we predicted.
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| Free Research Field |
医歯薬学
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