Journal Article

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

Nan Wang, Xiaoou Sun, Xiangyu Liu, Fang Kong, Brian K. Kobilka, Angqi Zhu, Jiawei Zhao, Yosuke Toyoda, Sisi Shan, Linqi Zhang, Chuangye Yan

2023

Overview

The α 1A- adrenergic receptor (α 1A AR) belongs to the family of G protein-coupled receptors that respond to adrenaline and noradrenaline. α 1A AR is involved in smooth muscle contraction and cognitive function. Here, we present three cryo-electron microscopy structures of human α 1A AR 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 α 1A AR 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 α 1A AR 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 1A -adrenergic receptor (α 1A AR) regulates smooth muscle contraction and cognitive functions. Here, authors provide structural insight into α 1A AR activation and binding modes of the orthosteric ligands and an extracellular allosteric nanobody.

• Publisher: Springer Science and Business Media LLC,Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/1 / 101/28 / 631/154/436/2387 / 631/45/612/194 / 631/535/1258/1259 / 82/80 / 82/83 / 96/95 / Adrenergic receptors / Agonists / Allosteric properties / Binding / Cognitive ability / Drug delivery / Drug development / Electron microscopy / G protein-coupled receptors / Humanities and Social Sciences / Ligands / multidisciplinary / Muscle contraction / Muscles / Muscular function / Nanobodies / Noradrenaline / Norepinephrine / Q / Receptor mechanisms / Receptors (physiology) / Science / Science (multidisciplinary) / Smooth muscle / Vestibules