Unique properties of coactivator recruitment caused by differential binding of FK614, an anti-diabetic agent, to peroxisome proliferator-activated receptor gamma

Biological & Pharmaceutical Bulletin
Takao FujimuraSeitaro Mutoh

Abstract

FK614 is a structurally novel class of peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, with the mechanism of its insulin-sensitizing action most likely due to activation of PPARgamma. In this study, properties of FK614 for PPARgamma binding, ability to induce conformational change, and coactivator recruitment were investigated. FK614, rosiglitazone, and pioglitazone competed specific binding of [3H]rosiglitazone to PPARgamma with Ki values of 11 nM, 47 nM, and 1.3 microM, respectively. Limited trypsin digestion of PPARgamma with FK614 or rosiglitazone produced distinct patterns of digested polypeptides, suggesting that FK614 directly binds to PPARgamma but induces specific alterations in receptor conformation. FK614 induced interaction of PPARgamma with nuclear receptor coactivator CBP but of lower magnitude than rosiglitazone and pioglitazone. The estimated Kd values of FK614-, rosiglitazone-, and pioglitazone-PPARgamma complex to CBP peptide were 1.8, 0.64, and 0.72 microM, respectively, indicating FK614-PPARgamma complex exhibits a lower affinity for CBP peptide compared to other agonist-PPARgamma complexes. When tested the effect of FK614 on CBP recruitment induced by 9(S)-hydroxyoctadecadienoic acid, ...Continue Reading

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Citations

Mar 14, 2013·Naunyn-Schmiedeberg's Archives of Pharmacology·Hanna KozłowskaBarbara Malinowska
Dec 17, 2009·Journal of Molecular Modeling·Vinicius G MaltarolloKathia M Honório
Oct 27, 2012·Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics·Qiong QinKonstantin Petrukhin
Jul 2, 2011·Biological & Pharmaceutical Bulletin·Kenji WakabayashiJun Ohsumi
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May 10, 2006·The Journal of Pharmacology and Experimental Therapeutics·Takao FujimuraSeitaro Mutoh
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Dec 7, 2020·Pharmacology Research & Perspectives·Youyi PengWilliam J Welsh
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