Back

John B. Bruning

John B. Bruning

The University of Adelaide, Australia

Title: Structural mechanism of partial agonists and antagonists of PPARgamma for use as antidiabetics

Biography

I received by BSc from Texas A&M University in 1997.  I began crystallography in the laboratory of Yousif Shamoo at Rice University.  During my graduate studies I worked on the structural mechanism of the human sliding clamp and its interactions with DNA replication proteins.  I received my PhD in 2005.  I completed 2 successful post-docs.  The first was at the Scripps Research Institute from 2005-2007 working on structural studies of nuclear receptors including PPAR, RXR, ER, and TR.  My second post-doc was with Jim Sacchettini in the Houston Medical centre and I was a part of the TB structural genomics consortium.  I received my first faculty position at the University of Adelaide in 2012 as a lecturer.  I was tenured in 2015 and promoted to Senior Lecturer in 2016.  Do to my continued collaboration with Scripps, I was also appointed adjunct professor of the Scripps Research Institute in 2016.

Abstract

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.

References:

  1. “X-ray Crystal Structure of Rivoglitazone bound to PPARγ and PPAR Subtype Selectivity of TZDs.” Rajapaksha H, Bhatia H, Wegener K, Petrovsky N, Bruning JB. Biochim Biophys Acta. (2017 May 9).
  2. “Structure-Activity Relationship of 2,4-Dichloro-N-(3,5-dichloro-4-(quinolin-3-yloxy)phenyl)benzenesulfonamide (INT131) Analogs for PPARγ-Targeted Antidiabetics.” Frkic RL, He Y, Rodriguez BB, Chang MR, Kuruvilla D, Ciesla A, Abell AD, Kamenecka TM, Griffin PR, Bruning JB. J Med Chem. (2017 May 22). 
  3. “PPARG Post-translational Modifications Regulate Bone Formation and Bone Resorption.” Stechschulte LA, Czernik PJ, Rotter ZC, Tausif FN, Corzo CA, Marciano DP, Asteian A, Zheng J, Bruning JB, Kamenecka TM, Rosen CJ, Griffin PR, Lecka-Czernik B. EBioMedicine. (2016 Aug;10:174-84).
  4. “SR2067 Reveals a Unique Kinetic and Structural Signature for PPARγ Partial Agonism.” van Marrewijk LM, Polyak SW, Hijnen M, Kuruvilla D, Chang MR, Shin Y, Kamenecka TM, Griffin PR, Bruning JB. ACS Chem Biol. (2016 Jan 15);11(1):273-83.
  5. “Structural mechanism for signal transduction in RXR nuclear    receptor heterodimers.” Kojetin DJ, Matta-Camacho E, Hughes TS, Srinivasan S, Nwachukwu JC, Cavett V, Nowak J, Chalmers MJ, Marciano DP, Kamenecka TM, Shulman AI, Rance M, Griffin PR, Bruning JB, Nettles KW. Nat Commun. (2015 Aug 20);6:8013.