Deciphering downstream receptor signaling

G protein-coupled receptors (GPCRs) are important cell-surface signaling proteins that are responsive to diverse extracellular stimuli and are key drug targets (1). Understanding how compounds activate GPCRs and modulate their interactions with intracellular proteins such as G proteins and beta-arrestins is crucial for drug discovery because these proteins transduce signals to downstream effectors, triggering biological responses. This includes elucidating the molecular details behind the ability of the drug-GPCR complex to generate a functional response (efficacy) and the concentration of the drug required to produce half-maximal response (potency) (2). Although agonist binding to a GPCR triggers conformational rearrangements throughout the receptor and its transducer (3), the molecular mechanisms that govern ligand efficacy and potency are difficult to ascertain. On page 1378 of this issue, Heydenreich et al. (4) explored how individual amino acids in the prototypical Gs-coupled beta 2-adrenergic receptor "interpret" information encoded in the atoms of its endogenous agonist, adrenaline, to drive its efficacy and potency.