Poster Presentation The 42nd Lorne Conference on Protein Structure and Function 2017

Structural mechanism of PPARgamma partial agonists and antagonists for use as antidiabetics (#180)

Rebecca Frkic 1 , Ted Kamenecka 2 , Patrick Griffin 2 , John B Bruning 3
  1. The University of Adelaide, Adelaide, SA, Australia
  2. The Scripps Research Institute, Jupiter, Florida, USA
  3. University of Adelaide, Adelaide, SA, Australia

Synthetic full agonists of PPARgamma 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 PPARgamma to date and little structural and dynamic information is available which can shed light on the mechanistic difference between full and partial agonists. We have used X-ray crystallography, cellular assays, Hydrogen Deuterium Exchange (HDX), and Surface Plasmon Resonance (SPR) to probe the mechanism of several PPARgamma 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.

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