Molecular recognition of nitrated fatty acids by PPAR gamma." Nat Struct Mol Biol 15(8

Peroxisome proliferator activated receptor-γ (PPARγ) regulates metabolic homeostasis and adipocyte differentiation, and it is activated by oxidized and nitrated fatty acids. Here we report the crystal structure of the PPARγ ligand binding domain bound to nitrated linoleic acid, a potent endogenous ligand of PPARγ. Structural and functional studies of receptor-ligand interactions reveal the molecular basis of PPARγ discrimination of various naturally occurring fatty acid derivatives. PPARγ is a nuclear receptor that regulates adipocyte differentiation and glucose homeostasis1. The synthetic PPARγ ligands rosiglitazone (Avandia) and pioglitazone (Actos) are thiazolidinedione derivatives (TZDs) used for the treatment of type 2 diabetes. Despite the importance of PPARγ in human physiology and drug discovery, the identity of physiological ligands remains elusive. The first implicated natural ligand of PPARγ was 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2), an oxidized fatty acid2,3. Later, 9-hydroxyoctadecadienoic acid (9-HODE) and 13-hydroxyoctadecadienoic acid (13-HODE), two oxidized fatty acids present in oxidized low-density lipoprotein, were shown to activat