The role of conformational ensembles of seven transmembrane receptors in functional selectivity

It has been observed that some ligands cause receptors to selectively interact with subsets of signaling proteins to 'bias' their signaling; this is inconsistent with receptors forming a single active state. Here we review the concept of receptor conformation ensembles that can account for a given agonist showing varied efficacies for different signaling pathways. Data show that agonists can stabilize different receptor conformations. We provide a demonstration at the molecular level of how the various receptor conformations in the ensemble can produce functional selectivity for signaling pathways. Specifically, agonists that selectively stabilize certain receptor conformations from the ensemble can produce biased agonism towards this signaling pathway. These ideas are described with data supported from recent computations of the potential energy surface of the β2-adrenergic receptor.