Cryo-EM structures of the β 3 adrenergic receptor bound to solabegron and isoproterenol

The β -adrenergic receptor (β AR) is the most essential drug target for overactive bladder and has therapeutic potentials for the treatments of type 2 diabetes and obesity. Here, we report the cryo-electron microscopy structures of the β AR-G signaling complexes with the selective agonist, solabegron and the nonselective agonist, isoproterenol. Comparison of the isoproterenol-, mirabegron-, and solabegron-bound β AR structures revealed that the extracellular loop 2 changes its conformation depending on the bound agonist and plays an essential role in solabegron binding. Moreover, β AR has an intrinsically narrow exosite, regardless of the agonist type. This structural feature clearly explains why β AR prefers mirabegron and solabegron, as the narrow exosite is suitable for binding with agonists with elongated shapes. Our study deepens the understanding of the binding characteristics of β AR agonists and may pave the way for developing β AR-selective drugs.