Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan.
Biochem Biophys Res Commun. 2022 Jun 30;611:158-164. doi: 10.1016/j.bbrc.2022.04.065. Epub 2022 Apr 19.
The β-adrenergic receptor (βAR) 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 βAR-G signaling complexes with the selective agonist, solabegron and the nonselective agonist, isoproterenol. Comparison of the isoproterenol-, mirabegron-, and solabegron-bound βAR structures revealed that the extracellular loop 2 changes its conformation depending on the bound agonist and plays an essential role in solabegron binding. Moreover, βAR has an intrinsically narrow exosite, regardless of the agonist type. This structural feature clearly explains why βAR 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 βAR agonists and may pave the way for developing βAR-selective drugs.
β-肾上腺素能受体（βAR）是治疗膀胱过度活动症的最重要药物靶点，并且在治疗 2 型糖尿病和肥胖症方面具有治疗潜力。在这里，我们报告了与选择性激动剂索利那新和非选择性激动剂异丙肾上腺素结合的βAR-G 信号复合物的低温电子显微镜结构。异丙肾上腺素、米拉贝隆和索利那新结合的βAR 结构的比较表明，细胞外环 2 根据结合的激动剂改变构象，并在索利那新结合中发挥重要作用。此外，βAR 具有内在的狭窄变构位点，与激动剂类型无关。这种结构特征清楚地解释了为什么βAR 更喜欢米拉贝隆和索利那新，因为狭窄的变构位点适合与具有拉长形状的激动剂结合。我们的研究加深了对βAR 激动剂结合特性的理解，并可能为开发βAR 选择性药物铺平道路。
