Defining a conformational ensemble that directs activation of PPARγ.

摘要: The nuclear receptor ligand-binding domain (LBD) is a highly dynamic entity. Crystal structures have defined multiple low-energy LBD structural conformations of the activation function-2 (AF-2) co-regulator-binding surface, yet it remains unclear how ligand binding influences number and population within AF-2 ensemble. Here, we present surface ensemble in solution, viewed through lens fluorine-19 (19F) magnetic resonance (NMR) molecular simulations, response this to ligands, co-regulator peptides heterodimerization. We correlate composition with function peroxisome proliferator-activated receptor-γ (PPARγ) utilizing ligands diverse efficacy recruitment. While apo PPARγ partial-agonist-bound characterized by thermodynamically accessible conformations, full inverse-agonist-bound restricted few which favor coactivator or corepressor binding, respectively.