Cryo-EM structures of the β3 adrenergic receptor bound to solabegron and isoproterenol

The beta(3)-adrenergic receptor (beta(3)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 cryoelectron microscopy structures of the beta(3)AR-Gs signaling complexes with the selective agonist, solabegron and the nonselective agonist, isoproterenol. Comparison of the isoproterenol-, mirabegron-, and solabegron-bound beta(3)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, beta(3)AR has an intrinsically narrow exosite, regardless of the agonist type. This structural feature clearly explains why beta(3)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 beta(3)AR agonists and may pave the way for developing R3AR-selective drugs. (C) 2022 The Authors. Published by Elsevier Inc.

Automated summary

This study reported the cryoelectron microscopy structures of beta(3)-adrenergic receptor (beta(3)AR) in complex with selective agonist solabegron and nonselective agonist isoproterenol. The structural analysis revealed the conformational changes of extracellular loop 2 depending on the bound agonist and the narrow exosite of beta(3)AR, which explains the receptor's preference for specific agonists with elongated shapes. This study deepens the understanding of beta(3)AR agonist binding characteristics and has implications for the development of selective drugs.