WEHI New Medicines and Diagnostics Special Seminar hosted by Dr Andrew Thompson

Dr John Bruning

Senior Lecturer – School of Biological Sciences, Faculty of Sciences, Engineering and Technology  - The University of Adelaide

PPARG modulators for the treatment of human disease

L7W Seminar Room | Bundoora Large Boardroom

Join via TEAMS

Including Q&A session

John B. Bruning is currently employed as an Associate Professor (with tenure) at the University of Adelaide where he heads the Laboratory of Protein Crystallography. He obtained his PhD at Rice University and completed two post-doctoral fellowships: one at the Scripps Research Institute and one at Texas A&M University. While at the Scripps Research Institute he spearheaded research on defining nuclear receptor allostery and structure guided drug design which he carried out in a world-renowned research environment. He conceived and carried out many multidisciplinary projects interacting with chemists, microbiologists, biochemists, endocrinologists, and structural biologists. While at Texas A&M University he played an integral part in the TB consortium and used the crystallographic facilities and mentoring available to solve more than 30 protein structures. In August 2012 he earned a highly competitive Lecturer faculty position in the School of Molecular and Biomedical Science (now the School of Biological Sciences) at the University of Adelaide. He has created and manages the first macromolecular crystal pipeline at the University of Adelaide North Terrace. CI Bruning is an expert in multiple areas of structural biology, especially in regard to the application of X-ray crystallography to understanding human disease. His work has been focused on areas such as protein sensor modulation, allostery, structure guided drug design, and protein structure using novel multidisciplinary approaches. He has characterized biochemical systems of varied but related areas such as nuclear receptors, DNA replication and repair proteins, enzymatic processes of microorganisms including inhibitor design, as well as method design for improving the ability to crystallize difficult to handle proteins as seen with the nuclear receptors.

Peroxisome Proliferator Activated Receptor γ (PPARγ) serves as a master regulator of human metabolism and plays a critical role in type 2 diabetes development. While full agonists like rosiglitazone effectively sensitize insulin, their clinical use is limited by severe adverse effects including bone density loss, weight gain, and cardiovascular complications. This has driven research toward alternative PPARγ modulators that maintain antidiabetic efficacy while minimizing side effects.  We have studied the structural, dynamic, allosteric and transcriptional mechanisms of PPARG modulation across various classes of compounds (i.e. agonists versus antagonists). Our findings demonstrate that PPARγ antagonists and inverse agonists operate through a distinct molecular mechanism that promotes corepressor recruitment while maintaining beneficial metabolic effects. The structural insights gained from this work advance our understanding of PPARγ modulation and provide a foundation for developing safer, more effective insulin sensitizers. This research contributes to the growing body of evidence supporting inverse agonists as promising therapeutic alternatives to traditional full agonists for type 2 diabetes treatment, offering the potential for improved patient outcomes with reduced adverse effects.

All welcome!