An allosteric modulator binds to a conformational hub in the ß2 adrenergic receptor.
Nat Chem Biol
; 16(7): 749-755, 2020 07.
Article
en En
| MEDLINE
| ID: mdl-32483378
ABSTRACT
Most drugs acting on G-protein-coupled receptors target the orthosteric binding pocket where the native hormone or neurotransmitter binds. There is much interest in finding allosteric ligands for these targets because they modulate physiologic signaling and promise to be more selective than orthosteric ligands. Here we describe a newly developed allosteric modulator of the ß2-adrenergic receptor (ß2AR), AS408, that binds to the membrane-facing surface of transmembrane segments 3 and 5, as revealed by X-ray crystallography. AS408 disrupts a water-mediated polar network involving E1223.41 and the backbone carbonyls of V2065.45 and S2075.46. The AS408 binding site is adjacent to a previously identified molecular switch for ß2AR activation formed by I3.40, P5.50 and F6.44. The structure reveals how AS408 stabilizes the inactive conformation of this switch, thereby acting as a negative allosteric modulator for agonists and positive allosteric modulator for inverse agonists.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Norepinefrina
/
Receptores Adrenérgicos beta 2
/
Antagonistas Adrenérgicos beta
/
Alprenolol
/
Agonistas de Receptores Adrenérgicos beta 2
/
Xinafoato de Salmeterol
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Nat Chem Biol
Asunto de la revista:
BIOLOGIA
/
QUIMICA
Año:
2020
Tipo del documento:
Article
País de afiliación:
China