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. We have undertaken a large scale structural study to identify the mechanism of partial agonism of PPARg.  By means of X-ray crystallography and Hydrogen Deuterium Exchange (HDX) experimentation on a large test set of partial agonists and full agonists we are dissecting the epitope specific signatures of these classes of compounds.  Initial results suggest that helix 12, helix 11, and the beta sheet region are specifically modulated in a differential manner between full and partial agonists of PPARg. These compounds show potent antidiabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the PPARγ drugs.