Molecular insight into the activator and deactivator mutations of peroxisome proliferator-activated receptor gamma.

The nuclear receptor known as peroxisome proliferator-activated receptor gamma (PPARγ) is essential for inflammation, lipid metabolism, glucose homeostasis, and adipogenesis. The function of PPARγ can be significantly impacted by mutations that either activate or deactivate the receptor. Deactivating variants can act as dominant-negative forms that sequester coactivators, impair ligand recognition, destabilize the activation function-2 (AF-2) surface, or favor corepressor binding. They are frequently found in the ligand-binding or DNA-binding domains. Metabolic disorders like severe insulin resistance and familial partial lipodystrophy type 3 are caused by these mutations. Activating mutations provide mechanistic insights into receptor overactivation by stabilizing helix 12 and the AF-2 surface, improving coactivator recruitment, and promoting ligand-independent transcription. These variations change the equilibrium between inactive and active states, modify coactivator binding, and reshape conformational ensembles, as demonstrated by molecular dynamics simulations. The design of selective modulators for precision therapy that target PPARγ is guided by an understanding of these molecular mechanisms, which also help classify mutations as dominant-negative or drug-rescuable.