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关键词： G-PROTEIN   BETA(3)-ADRENERGIC RECEPTOR   CRYSTAL-STRUCTURE   GENETIC-VARIATION   DYNAMIC PROCESS   FORCE-FIELD   GS-PROTEIN   AGONIST   INSIGHTS   FEATURES  

摘要： The beta(3)-adrenergic receptor (beta(3)AR) 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 (beta(3)AR-Gs signaling complex with the selective agonist mirabegron, a first-in-class drug for OAB. Comparison of this structure with the previously reported (beta(3)AR and beta(3)AR structures reveals a receptor activation mechanism upon mirabegron binding to the orthosteric site. Notably, the narrower exosite in beta(3)AR 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 beta(3)AR agonists. Our findings provide a molecular basis for beta(3)AR subtype selectivity, allowing the design of more-selective agents with fewer adverse effects.

关键词： 道路桥梁   伸缩缝   施工技术  

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