Identification of an allosteric hotspot for additive activation of PPARγ in antidiabetic effects

Abstract Thiazolidinediones (TZDs), such as rosiglitazone (RSG), which activates peroxisome proliferator activated receptor-γ (PPARγ), are a potent class of oral antidiabetic agents with good durability. However, the clinical use of TZDs is challenging because of their side effects, including weight gain and hepatotoxicity. Here, we found that bavachinin (BVC), a lead natural product, additively activates PPARγ with low-dose RSG to preserve the maximum antidiabetic effects while reducing weight gain and hepatotoxicity in db/db mice caused by RSG monotherapy. Structural and biochemical assays demonstrated that an unexplored hotspot around Met329 and Ser332 in helix 5 is triggered by BVC cobinding to RSG-bound PPARγ, thereby allosterically stabilizing the active state of the activation-function 2 motif responsible for additive activation with RSG. Based on this hotspot, we discovered a series of new classes of allosteric agonists inducing the activity of TZDs in the same manner as BVC. Together, our data illustrate that the hotspot of PPARγ is druggable for the discovery of new allosteric synergists, and the combination therapy of allosteric synergists and TZD drugs may provide a potential alternative approach to the treatment of type 2 diabetes mellitus.