National Center for
4A4V: Ligand Binding Domain Of Human Ppar Gamma In Complex With Amorfrutin 2
Structural characterization of amorfrutins bound to the peroxisome proliferator-activated receptor gamma
J. Med. Chem. (2013) 56 p.1535-1543
Amorfrutins are a family of natural products with high affinity to the peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor regulating lipid and glucose metabolism. The PPARgamma 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 PPARgamma 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 PPARgamma but not helix H12.