Peroxisome proliferator-activated receptor gamma (PPAR¿) is a nuclear receptor transcription factor that
regulates cellular differentiation, adipogenesis, and insulin resistance by recruiting transcriptional coregulator
proteins (corepressor and coactivator proteins) to target gene promoters in a ligand-dependent manner.
Structure-function approaches have defined how the transcriptionally active structural conformation and
coactivator-selective functions of PPAR¿ are influenced by agonist ligands. However, little is known about the
transcriptionally repressive conformation and corepressor-selective functions of PPAR¿. Our long-term goal is
to close this knowledge gap by defining how different pharmacological PPAR¿ ligands influence the structure
and function of PPAR¿ between transcriptionally active and repressive states. In preliminary studies, we solved
crystal structures of the PPAR¿ ligand-binding domain (LBD) in a transcriptionally repressive state using a
unique corepressor-selective ligand, revealing a unique structural conformation that we have started to validate
using solution NMR methods. In this project, we will use mechanistic studies to define how small molecule
ligands impact PPAR¿ activation and repression on the molecular, structural, and cellular levels. Successful
outcomes from our studies will define the activity-dependent conformational ensemble of the PPAR¿ LBD,
develop ligands with enhanced corepressor-selective activity, and determine the molecular mechanisms by
which corepressor-selective repressive ligands modulate PPAR¿ cellular functions.