 The 1A adrenergic receptor, 1AAR, is a G-protein-coupled receptor that responds to adrenaline and noadrenaline. It plays a role in smooth muscle contraction and cognition. Three cryo-electron microscopy structures of human 1AAR were obtained, each with different resolutions ranging from 2.98 to 3.5A. The structures revealed the activation mechanism and distinct ligand binding modes for noadrenaline compared with other adrenergic receptor subtypes. Additionally, a nanobody was identified which preferentially binds to the extracellular vestibule of 1AAR when bound to the selective agonist oxymetazoline. This information will help in the development of more selective therapeutics targeting both orthosteric and allosteric sites in this receptor family. This article was authored by Yosuke Toyoda, Anki Zhu, Fang Kong, and others.