Cryo-EM structures of the β3 adrenergic receptor bound to solabegron and isoproterenol
Cryo-EM structures of the β3 adrenergic receptor bound to solabegron and isoproterenol
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与索拉贝隆和异丙肾上腺素结合的 β3 肾上腺素受体的冷冻电镜结构
DOI：
10.1016/j.bbrc.2022.04.065
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发表时间：
2022
影响因子：
3.1
通讯作者：
Nureki Osamu
中科院分区：
文献类型：
--
作者：
Nureki Ikko;Kobayashi Kazuhiro;Tanaka Tatsuki;Demura Kanae;Inoue Asuka;Shihoya Wataru;Nureki Osamu
β3-肾上腺素能受体（β 3-adrenergic receptor，β3AR）是治疗膀胱过度活动症最重要的药物靶点，在2型糖尿病和肥胖症的治疗中具有潜在的应用价值。本文报道了选择性激动剂索拉贝隆和非选择性激动剂异丙肾上腺素与β 3AR-GS信号复合物的冷冻电镜结构。异丙肾上腺素、米拉贝隆和索拉贝隆结合的β3AR结构的比较显示，细胞外环2根据结合的激动剂改变其构象，并在索拉贝隆结合中发挥重要作用。此外，β3AR具有固有的狭窄外位点，无论激动剂类型如何。这种结构特征清楚地解释了为什么β3AR更喜欢米拉贝隆和索拉贝隆，因为狭窄的外位点适合与细长形状的激动剂结合。本研究加深了对β 3 AR激动剂结合特性的认识，为开发β 3 AR选择性药物奠定了基础。
The β3-adrenergic receptor (β3AR) 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 β3AR-Gssignaling complexes with the selective agonist, solabegron and the nonselective agonist, isoproterenol. Comparison of the isoproterenol-, mirabegron-, and solabegron-bound β3AR structures revealed that the extracellular loop 2 changes its conformation depending on the bound agonist and plays an essential role in solabegron binding. Moreover, β3AR has an intrinsically narrow exosite, regardless of the agonist type. This structural feature clearly explains why β3AR 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 β3AR agonists and may pave the way for developing β3AR-selective drugs.