title: Structural basis for the activation of PPARgamma by oxidized fatty acids.
abstract: The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) has important roles in adipogenesis and immune response as well as roles in both lipid and carbohydrate metabolism. Although synthetic agonists for PPARgamma are widely used as insulin sensitizers, the identity of the natural ligand(s) for PPARgamma is still not clear. Suggested natural ligands include 15-deoxy-delta12,14-prostaglandin J2 and oxidized fatty acids such as 9-HODE and 13-HODE. Crystal structures of PPARgamma have revealed the mode of recognition for synthetic compounds. Here we report structures of PPARgamma bound to oxidized fatty acids that are likely to be natural ligands for this receptor. These structures reveal that the receptor can (i) simultaneously bind two fatty acids and (ii) couple covalently with conjugated oxo fatty acids. Thermal stability and gene expression analyses suggest that such covalent ligands are particularly effective activators of PPARgamma and thus may serve as potent and biologically relevant ligands.
authors.affiliation: Henry Wellcome Laboratories of Structural Biology, Department of Biochemistry, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Itoh
authors.forename: Louise
authors.initials: L
authors.lastname: Fairall
authors.forename: Kush
authors.initials: K
authors.lastname: Amin
authors.forename: Yuka
authors.initials: Y
authors.lastname: Inaba
authors.forename: Attila
authors.initials: A
authors.lastname: Szanto
authors.forename: Balint L
authors.initials: BL
authors.lastname: Balint
authors.forename: Laszlo
authors.initials: L
authors.lastname: Nagy
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: John W R
authors.initials: JW
authors.lastname: Schwabe
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D019556:COS Cells; D002522:Chlorocebus aethiops; D003545:Cysteine / Q000737:chemistry; D005227:Fatty Acids / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D046911:Macromolecular Substances / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D010084:Oxidation-Reduction; D047495:PPAR gamma / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055672:Static Electricity
chemical_list: D005227:Fatty Acids; D008024:Ligands; D046911:Macromolecular Substances; D047495:PPAR gamma; D011994:Recombinant Proteins; D003545:Cysteine