School of Medicine, Tsinghua University, Beijing, 100084, China.
Beijing Frontier Research Center for Biological Structure, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, 100084, China.
Nat Commun. 2023 Jun 20;14(1):3655. doi: 10.1038/s41467-023-39310-x.
The αadrenergic receptor (αAR) belongs to the family of G protein-coupled receptors that respond to adrenaline and noradrenaline. αAR is involved in smooth muscle contraction and cognitive function. Here, we present three cryo-electron microscopy structures of human αAR bound to the endogenous agonist noradrenaline, its selective agonist oxymetazoline, and the antagonist tamsulosin, with resolutions range from 2.9 Å to 3.5 Å. Our active and inactive αAR structures reveal the activation mechanism and distinct ligand binding modes for noradrenaline compared with other adrenergic receptor subtypes. In addition, we identified a nanobody that preferentially binds to the extracellular vestibule of αAR when bound to the selective agonist oxymetazoline. These results should facilitate the design of more selective therapeutic drugs targeting both orthosteric and allosteric sites in this receptor family.
α 肾上腺素能受体 (αAR) 属于 G 蛋白偶联受体家族，对肾上腺素和去甲肾上腺素有反应。αAR 参与平滑肌收缩和认知功能。在这里，我们展示了三种人类 αAR 与内源性激动剂去甲肾上腺素、其选择性激动剂奥昔布宁和拮抗剂坦索罗辛结合的冷冻电镜结构，分辨率范围从 2.9 Å 到 3.5 Å。我们的活性和非活性 αAR 结构揭示了与其他肾上腺素能受体亚型相比，去甲肾上腺素的激活机制和独特的配体结合模式。此外，我们鉴定了一种纳米抗体，当与选择性激动剂奥昔布宁结合时，该纳米抗体优先结合到 αAR 的细胞外前庭。这些结果应该有助于设计针对该受体家族的正位和变构位点的更具选择性的治疗药物。
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