Figure 7. Schematic model of agonist binding to a dynamic apo-PPARγ LBD conformational ensemble via a two-step process involving an initial fast step followed by a slow conformational change step.

In the absence of ligand, helix 12 in apo-PPARγ LBD exchanges between a transcriptionally repressive conformation within the orthosteric ligand-binding pocket and a solvent exposed active conformation. Agonist binding to the ligand entry site via an encounter complex could occur to either of these conformations. In the pure induced fit scenario, agonist binding to the repressive LBD conformation would push helix 12 into an active conformation. In the mixed induced fit & conformational selection scenario, ligand binding to the active LBD conformation would facilitate transition into the final ligand binding pose. Structures displayed include PDB code 6ONJ (active conformation; chain A), 6ONI (repressive conformation; chain B), and 6DGL (darglitazone ligand; chain B). Black arrows denote processes supported by experimental studies (NMR, SPR, and ITC heat capacity analysis); grey arrows denote other steps that are part of the binding kinetic pathways.