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Alteration of a Single Amino Acid in Peroxisome Proliferator-Activated Receptor- (PPAR) Generates a PPAR Phenotype

Graduate School for Biostudies Kyoto University (I.T., R.T.Y., K.U.) Kyoto 606-8507, Japan
Glaxo Wellcome Inc. Research and Development (H.E.X., M.H.L., V.G.M., S.A.K.) Research Triangle Park, North Carolina 27709
Howard Hughes Medical Institute (R.M.E.) The Salk Institute for Biological Studies La Jolla, California 92037

Three pharmacologically important nuclear receptors, the peroxisome proliferator-activated receptors (PPARs , , and ), mediate key transcriptional responses involved in lipid homeostasis. The PPAR and subtypes are well conserved from Xenopus to man, but the ß/ subtypes display substantial species variations in both structure and ligand activation profiles. Characterization of the avian cognates revealed a close relationship between chick (c) and subtypes to their mammalian counterparts, whereas the third chicken subtype was intermediate to Xenopus (x) ß and mammalian , establishing that ß and are orthologs. Like xPPARß, cPPARß responded efficiently to hypolipidemic compounds that fail to activate the human counterpart. This provided the opportunity to address the pharmacological problem as to how drug selectivity is achieved and the more global evolutionary question as to the minimal changes needed to generate a new class of receptor. X-ray crystallography and chimeric analyses combined with site-directed mutagenesis of avian and mammalian cognates revealed that a Met to Val change at residue 417 was sufficient to switch the human and chick phenotype. These results establish that the genetic drive to evolve a novel and functionally selectable receptor can be modulated by a single amino acid change and suggest how nuclear receptors can accommodate natural variation in species physiology.

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