Structural basis of α1A-adrenergic receptor activation and recognition by an extracellular nanobody

Yosuke Toyoda (), Angqi Zhu, Fang Kong, Sisi Shan, Jiawei Zhao, Nan Wang, Xiaoou Sun, Linqi Zhang, Chuangye Yan (), Brian K. Kobilka () and Xiangyu Liu ()
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Yosuke Toyoda: Tsinghua University
Angqi Zhu: Tsinghua University
Fang Kong: Tsinghua University
Sisi Shan: Tsinghua University
Jiawei Zhao: Tsinghua University
Nan Wang: Tsinghua University
Xiaoou Sun: Tsinghua University
Linqi Zhang: Tsinghua University
Chuangye Yan: Tsinghua University
Brian K. Kobilka: Stanford University School of Medicine
Xiangyu Liu: Tsinghua University

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract The α1A-adrenergic receptor (α1AAR) belongs to the family of G protein-coupled receptors that respond to adrenaline and noradrenaline. α1AAR is involved in smooth muscle contraction and cognitive function. Here, we present three cryo-electron microscopy structures of human α1AAR 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 α1AAR 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 α1AAR 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.

Date: 2023
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DOI: 10.1038/s41467-023-39310-x

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