Agonist-induced conformational changes in the β2 adrenergic receptor

G-protein-coupled receptors (GPCRs) are nature's most versatile biological sensors and are responsible for the majority of cellular responses to hormones and neurotransmitters, as well as for the senses of sight, smell and taste. Despite diverse physiologic roles, the majority of GPCRs are thought to share a common activation mechanism. Our current models of the mechanism of GPCR activation by diffusible agonists have been deduced from indirect measures of receptor conformation, such as G-protein or second messenger activation (1-4). These indirect assays of GPCR activity provide only limited insight into the agonist-induced structural changes that define the active state of the receptor. For all known GPCRs, the site of ligand binding is distant from the site G-protein regulation (5). Therefore, the overall structural effects of agonists binding to extracellular sequences or transmembrane domains must physically converge at the cytoplasmic interface between the receptor and its G-protein.