Substitution of a conserved amino acid residue alters the ligand binding properties of peroxisome proliferator activated receptors

Mutation of glutamic acid 282 of PPAR alpha to glycine has been shown to result in an increased EC50 for a wide variety of PPAR activating compounds. This has suggested that mutant receptor has a reduced ability to bind ligand. In this study we show that this mutation reduces the affinity of mPPAR alpha and hPPAR gamma for the fluorescent fatty acid, cis-parinaric acid and that the mutant hPPAR gamma protein has:a reduced affinity for the radiolabelled compound, SB236636. These data confirm the role of this glutamic acid in ligand binding and support recent crystal structure observations regarding a proposed novel mode of ligand entry into the PPAR ligand binding cavities. (C) 1999 Federation of European Biochemical Societies.