Structural highlights
This is an X-ray crystallography structure, solved at 1.95 Å, which models the region of PPARδ from Gln171 to Tyr441[1]. It is composed of twelve alpha helices, with one small beta sheet region. The structure is bound to a synthetic ligand, GW0742, 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 three arms (Arm I residues are green, Arm II residues are blue, Arm III residues are red), with fifteen residues that contact the ligand. Arm I interacts with the ligand through Phe246, Cys249, His287, Phe291, Ile327, His413, Leu433, and Tyr437. The hydrophilic head of the ligand interacts via polar contacts with Arm I residues His287, His413, and Tyr437. Arm II, includes residues Val245, Val305, Val312, Leu317, and Ile 328, while Arm III includes Leu249 and Thr252. The hydrophobic tail 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 methionine, the authors found that two LBP residues from Arm II, Val312 and Ile328, are key to the specificity of this ligand for PPARδ.
Function
PPARs are ligand-activated transcription factors[2]. Activation of PPARδ (formerly called PPARβ) improves overall metabolic health.
Disease
PPARδ agonists are being investigated as treatments for metabolic disorders including dyslipidemia, Type 2 Diabetes, and cardiovascular disease.
Relevance
