RT Journal Article SR Electronic T1 The Differential Interactions of Peroxisome Proliferator-Activated Receptor γ Ligands with Tyr473 Is a Physical Basis for Their Unique Biological Activities JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 62 OP 74 DO 10.1124/mol.107.041202 VO 73 IS 1 A1 Monica Einstein A1 Taro E. Akiyama A1 Gino A. Castriota A1 Chuanlin F. Wang A1 Brian McKeever A1 Ralph T. Mosley A1 Joseph W. Becker A1 David E. Moller A1 Peter T. Meinke A1 Harold B. Wood A1 Joel P. Berger YR 2008 UL http://molpharm.aspetjournals.org/content/73/1/62.abstract AB Despite their proven antidiabetic efficacy, widespread use of peroxisome proliferator-activated receptor (PPAR)γ agonists has been limited by adverse cardiovascular effects. To overcome this shortcoming, selective PPARγ modulators (SPPARγMs) have been identified that have antidiabetic efficacy comparable with full agonists with improved tolerability in preclinical species. The results of structural studies support the proposition that SPPARγMs interact with PPARγ differently from full agonists, thereby providing a physical basis for their novel activities. Herein, we describe a novel PPARγ ligand, SPPARγM2. This compound was a partial agonist in a cell-based transcriptional activity assay, with diminished adipogenic activity and an attenuated gene signature in cultured human adipocytes. X-ray cocrystallography studies demonstrated that, unlike rosiglitazone, SPPARγM2 did not interact with the Tyr473 residue located within helix 12 of the ligand binding domain (LBD). Instead, SPPARγM2 was found to bind to and activate human PPARγ in which the Tyr473 residue had been mutated to alanine (hPPARγY473A), with potencies similar to those observed with the wild-type receptor (hPPARγWT). In additional studies, we found that the intrinsic binding and functional potencies of structurally distinct SPPARγMs were not diminished by the Y473A mutation, whereas those of various thiazolidinedione (TZD) and non-TZD PPARγ full agonists were reduced in a correlative manner. These results directly demonstrate the important role of Tyr473 in mediating the interaction of full agonists but not SPPARγMs with the PPARγ LBD, thereby providing a precise molecular determinant for their differing pharmacologies. The American Society for Pharmacology and Experimental Therapeutics