Structural highlights
This is an X-ray crystallography structure, with a resolution of 1.95 Å, which models the region of PPARδ from Gln171 to Tyr441[2]. It is composed of , with one small . The structure is bound to a synthetic ligand, , which contains a carboxylate group, a thiophenol, a thiazole, and a fluorine substituted phenyl ring. This ligand can be divided into a hydrophilic head group (carboxylate) and a hydrophobic tail (thiophenol, thiazole, phenyl). There is also a glycerol molecule in the structure, which is an artifact of the crystallization process and is not biologically relevant.
The ligand binding pocket (LBP) is made of (Arm I residues are green, Arm II residues are blue, Arm III residues are red), with fifteen residues that contact the ligand. interacts with the ligand through Phe246, Cys249, His287, Phe291, Ile327, His413, Leu433, and Tyr437. The of the ligand interacts via polar contacts with Arm I residues His287, His413, and Tyr437. , includes residues Val245, Val305, Val312, Leu317, and Ile 328, while includes Leu249 and Thr252. The of the ligand interacts via nonpolar contacts with residues from all three arms (Phe246, Phe291, His 413, Ile327, Leu433, Cys249, Val245, Val305, Val312, Leu317, Ile328, Thr252, and Leu294).
Using site-directed mutagenesis to replace LBP amino acids with Met, the authors found that from Arm II, Val312 and Ile328, are key to the specificity of this ligand for PPARδ.
Function
PPARs are ligand-activated transcription factors. These receptors are activated by a number of endogenous lipids, but synthetic ligands have also been developed for therapeutic use[3]. After activation, PPAR forms a heterodimer with the Retinoid X receptor, and the complex binds to DNA, either stimulating or repressing transcription of genes involved in glucose or lipid metabolism.
PPARδ is found in many tissues, but is most highly expressed in the gut, kidney, and heart[4]. It is activated by fatty acids, triglycerides, prostacyclin, and retinoic acid[5]. Though it is the least studied PPAR, its known functions include regulating acyl-CoA synthetase 2 expression and mediating embryo implantation[6][7].
Disease
PPARδ agonists are being investigated as treatments for a number of metabolic disorder and cardiovascular disorders, but have not yet been deployed clinically. Current literature suggests that PPARδ agonists could enhance fatty acid oxidation in skeletal muscle, reduce serum triglycerides, increase serum HDL levels, and enhance weight loss[8]. Though there are some health benefits associated with PPARα and γ agonists, these drugs also have undesirable side effects including such as edema and weight gain, and carcinogenicity in rodents[9][10]. If PPARδ agonists are to be used clinically, it is thus important to develop a ligand that does not also bind to the other PPARs.
