Article abstract
Nature Structural & Molecular Biology 15, 924 - 931 (2008)
Published online: 17 August 2008 | doi:10.1038/nsmb.1474
Structural basis for the activation of PPAR
by oxidized fatty acids
Toshimasa Itoh1, Louise Fairall1, Kush Amin1, Yuka Inaba2, Attila Szanto3, Balint L Balint3, Laszlo Nagy3, Keiko Yamamoto2 & John W R Schwabe1
Abstract
The nuclear receptor peroxisome proliferator–activated receptor-
(PPAR) has important roles in adipogenesis and immune response as well as roles in both lipid and carbohydrate metabolism. Although synthetic agonists for PPAR are widely used as insulin sensitizers, the identity of the natural ligand(s) for PPAR is still not clear. Suggested natural ligands include 15-deoxy-
12,14-prostaglandin J2 and oxidized fatty acids such as 9-HODE and 13-HODE. Crystal structures of PPAR have revealed the mode of recognition for synthetic compounds. Here we report structures of PPAR 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 PPAR and thus may serve as potent and biologically relevant ligands.
- Henry Wellcome Laboratories of Structural Biology, Department of Biochemistry, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
- Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, 3-3165 Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan.
- Apoptosis and Genomics Research Group of the Hungarian Academy of Sciences, Department of Biochemistry and Molecular Biology, Life Sciences Building, Medical and Health Science Center, University of Debrecen, Debrecen, Egyetem ter 1. H-4032 Hungary.
Correspondence to: John W R Schwabe1 e-mail: john.schwabe@le.ac.uk
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