Analysis of the Critical Structural Determinant(s) of Species-Selective Peroxisome Proliferator-Activated Receptor Alpha (PPARα)-Activation by Phenylpropanoic Acid-Type PPARα Agonists

In order to identify the critical structural feature(s) of phenylpropanoic acid-type PPARα agonists, such as KCL, which exhibit human peroxisome proliferator-activated receptor alpha (PPARα)-selective activation, transient transactivation assay of KCL and related derivatives was performed with PPARα containing wild-type and point-mutated (I272F or T279M) ligand-binding domain. The results indicated that the interaction of the distal hydrophobic tail part of KCL and related derivatives with amino acid residue 272 (isoleucine) in the helix three region of PPARα is of primary importance for human-selective PPARα activation.