Cryo-EM structure of the β3-adrenergic receptor reveals the molecular basis of subtype selectivity

The β₃-adrenergic receptor (β₃AR) is predominantly expressed in adipose tissue and urinary bladder and has emerged as an attractive drug target for the treatment of type 2 diabetes, obesity, and overactive bladder (OAB). Here, we report the cryogenic electron microscopy structure of the β₃AR-G_s signaling complex with the selective agonist mirabegron, a first-in-class drug for OAB. Comparison of this structure with the previously reported β₁AR and β₂AR structures reveals a receptor activation mechanism upon mirabegron binding to the orthosteric site. Notably, the narrower exosite in β₃AR creates a perpendicular pocket for mirabegron. Mutational analyses suggest that a combination of both the exosite shape and the amino-acid-residue substitutions defines the drug selectivity of the βAR agonists. Our findings provide a molecular basis for βAR subtype selectivity, allowing the design of more-selective agents with fewer adverse effects.