The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2018

Structural mechanism of antagonists and partial agonists of PPARgamma for use as antidiabetics (#179)

Ted Kamenecka 1 , Patrick R Griffin 1 , John B Bruning 2
  1. The Scripps Research Institute, Jupiter, Florida, USA
  2. The University of Adelaide, Adelaide, SA, Australia

Synthetic full agonists of PPARγ have been prescribed for the treatment of diabetes due to their ability to regulate glucose homeostasis and insulin sensitization. While the use of full agonists of PPARγ has been hampered due to severe side effects, partial agonists and antagonists have shown promise due to their decreased incidence of such side effects in preclinical models. No kinetic information has been forthcoming in regard to the mechanism of full versus partial agonism of PPARγ to date and little structural and dynamic information is available which can shed light on the mechanistic difference between full and partial agonists as well as antagonists. We have used X-ray crystallography, cellular assays, Hydrogen Deuterium Exchange (HDX), and Surface Plasmon Resonance (SPR) to probe the mechanism of several PPARγ partial agonists and antagonists. Our findings demonstrate that not only do partial agonists and antagonists act through distinct transcriptional mechanisms, they also demonstrate differences in structure, dynamics, and kinetics as compared to full agonists.