Quantitative Structural Assessment of Graded Receptor Agonism

摘要: ABSTRACT Ligand-receptor interactions, which are ubiquitous in physiology, described by theoretical models of receptor pharmacology. Structural evidence for graded-efficacy conformations predicted theory has been limited, but is critical to fully validate models. We applied quantitative structure-function approaches characterize the effects structurally similar and diverse agonists on conformational ensemble nuclear peroxisome proliferator-activated gamma (PPARγ). For all ligands, agonist efficacy correlated a shift equilibrium from ground state towards an active state, detected NMR spectroscopy not observed crystal structures. ligand potency also conformation, indicating residence times among related analogs can influence conformation function. Our results derived graded activity-conformation correlations provide new experimental platform with extend test pharmacology more accurately describe predict ligand-dependent activity.