Activation processes in ligand‐activated G protein‐coupled receptors: A case study of the adenosine A2A receptor

Here we review concepts related to an ensemble description of G-protein-coupled receptors (GPCRs). The ensemble is characterized by both inactive and active states, whose equilibrium populations and exchange rates depend sensitively on ligand, environment, and allosteric factors. This review focuses on the adenosine A2 receptor (A2AR), a prototypical class A GPCR. 19F Nuclear Magnetic Resonance (NMR) studies show that apo A2AR is characterized by a broad ensemble of conformers, spanning inactive to active states, and resembling states defined earlier for rhodopsin. In keeping with ideas associated with a conformational selection mechanism, addition of agonist serves to allosterically restrict the overall degrees of freedom at the G protein binding interface and bias both states and functional dynamics to facilitate G protein binding and subsequent activation. While the ligand does not necessarily “induce” activation, it does bias sampling of states, increase the cooperativity of the activation process and thus, the lifetimes of functional activation intermediates, while restricting conformational dynamics to that needed for activation.