Structural basis of α1A-adrenergic receptor activation and recognition by an extracellular nanobody.
Nat Commun
; 14(1): 3655, 2023 06 20.
Article
em En
| MEDLINE
| ID: mdl-37339967
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Oximetazolina
/
Receptores Adrenérgicos alfa 1
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article