Structural Characterization of Amorfrutins Bound to the Peroxisome Proliferator-Activated Receptor γ

Amorfrutins are a family of natural products with high affinity to the peroxisome proliferator-activated receptor gamma (PPAR gamma), a nuclear receptor regulating lipid and glucose metabolism. The PPAR gamma 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 gamma 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 beta-sheet of PPARy gamma but not helix H12.