Structural Characterization of Amorfrutins Bound to the Peroxisome Proliferator-Activated Receptor 纬
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- 作者：Jens C. de Groot ; Christopher Weidner ; Joern Krausze ; Ken Kawamoto ; Frank C. Schroeder ; Sascha Sauer ; Konrad B眉ssow
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：February 28, 2013
- 年：2013
- 卷：56
- 期：4
- 页码：1535-1543
- 全文大小：534K
- 年卷期：v.56,no.4(February 28, 2013)
- ISSN：1520-4804
文摘
Amorfrutins are a family of natural products with high affinity to the peroxisome proliferator-activated receptor 纬 (PPAR纬), a nuclear receptor regulating lipid and glucose metabolism. The PPAR纬 agonist rosiglitazone increases insulin sensitivity and is effective against type II diabetes but has severe adverse effects including weight gain. Amorfrutins improve insulin sensitivity and dyslipidemia but do not enhance undesired fat storage. They bear potential as therapeutics or prophylactic dietary supplements. We identified amorfrutin B as a novel partial agonist of PPAR纬 with a considerably higher affinity than that of previously reported amorfrutins, similar to that of rosiglitazone. Crystal structures reveal the geranyl side chain of amorfrutin B as the cause of its particularly high affinity. Typical for partial agonists, amorfrutins 1, 2, and B bind helix H3 and the 尾-sheet of PPAR纬 but not helix H12.