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Structural characterization of amorfrutins bound to the peroxisome proliferator-activated receptor γ

Item Type:Article
Title:Structural characterization of amorfrutins bound to the peroxisome proliferator-activated receptor γ
Creators Name:de Groot, J.C. and Weidner, C. and Krausze, J. and Kawamoto, K. and Schroeder, F.C. and Sauer, S. and Büssow, K.
Abstract:Amorfrutins are a family of natural products with high affinity to the peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor regulating lipid and glucose metabolism. The PPARγ 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 PPARγ 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 β-sheet of PPARγ but not helix H12.
Keywords:Drug Partial Agonism, HEK293 Cells, Molecular Structure, PPAR gamma, Reporter Genes, Salicylates, Stereoisomerism, X-Ray Crystallography
Source:Journal of Medicinal Chemistry
ISSN:0022-2623
Publisher:American Chemical Society (U.S.A.)
Volume:56
Number:4
Page Range:1535-1543
Date:28 February 2013
Official Publication:https://doi.org/10.1021/jm3013272
PubMed:View item in PubMed

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