title: Structural characterization of amorfrutins bound to the peroxisome proliferator-activated receptor γ.
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.
authors.affiliation: Department of Molecular Structural Biology, Helmholtz Centre for Infection Research, 38214 Braunschweig, Germany.
authors.forename: Jens C
authors.initials: JC
authors.lastname: de Groot
authors.forename: Christopher
authors.initials: C
authors.lastname: Weidner
authors.forename: Joern
authors.initials: J
authors.lastname: Krausze
authors.forename: Ken
authors.initials: K
authors.lastname: Kawamoto
authors.forename: Frank C
authors.initials: FC
authors.lastname: Schroeder
authors.forename: Sascha
authors.initials: S
authors.lastname: Sauer
authors.forename: Konrad
authors.initials: K
authors.lastname: Büssow
mesh_terms: D018360:Crystallography, X-Ray; D054333:Drug Partial Agonism; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D047495:PPAR gamma / Q000819:agonists / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012459:Salicylates / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D047495:PPAR gamma; D012459:Salicylates; C582540:amorfrutin B