Despite the clinical benefit of diabetic therapeutics such as the TZD (thiazolidinedione) compound class, their use has been associated with adverse effects including weight gain, increased adipogenesis, renal fluid retention, plasma volume expansion and possible increased incidence of cardiovascular events.  The nuclear receptor PPARγ (Peroxisome Proliferator-Activated Receptor) is the target of antidiabetic compounds such as the full agonist TZDs.  Partial agonists, however, have been shown to have lessened side effects and act through different structural mechanisms than full agonists.  Our work has revealed many of the structural and dynamic characteristics of partial agonists.  Additionally, the antidiabetic activity of PPARγ modulators correlates with their ability to block phosphorylation of PPARγ at Serine-273.  We discovered a high affinity PPARγ ligand, SR1664, which lacks any agonist activity and blocks S273 phosphorylation.  SR1664 demonstrates antidiabetic efficacy in vivo with reduced side effects revealing that agonism and antidiabetic action can be separated.  We have solved the crystal structure of the PPARγ LBD-SR1664 complex and performed HDX (hydrogen deuterium exchange) of the complex to monitor dynamics.  Our results suggest that SR1664 disrupts the PPARγ-RXRα heterodimer interface.  To confirm this hypothesis, we have made mutations in helix 11 that are consistent with the effect of SR1664.  Together our data provides insight into the structural mechanism of this class of antidiabetic modulators which target PPARγ.