Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation.
Nat Commun
; 12(1): 815, 2021 02 05.
Article
em En
| MEDLINE
| ID: mdl-33547286
ABSTRACT
Narcolepsy type 1 (NT1) is a chronic neurological disorder that impairs the brain's ability to control sleep-wake cycles. Current therapies are limited to the management of symptoms with modest effectiveness and substantial adverse effects. Agonists of the orexin receptor 2 (OX2R) have shown promise as novel therapeutics that directly target the pathophysiology of the disease. However, identification of drug-like OX2R agonists has proven difficult. Here we report cryo-electron microscopy structures of active-state OX2R bound to an endogenous peptide agonist and a small-molecule agonist. The extended carboxy-terminal segment of the peptide reaches into the core of OX2R to stabilize an active conformation, while the small-molecule agonist binds deep inside the orthosteric pocket, making similar key interactions. Comparison with antagonist-bound OX2R suggests a molecular mechanism that rationalizes both receptor activation and inhibition. Our results enable structure-based discovery of therapeutic orexin agonists for the treatment of NT1 and other hypersomnia disorders.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peptídeos
/
Sulfonamidas
/
Azepinas
/
Triazóis
/
Receptores de Orexina
/
Antagonistas dos Receptores de Orexina
/
Medicamentos Indutores do Sono
/
Aminopiridinas
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article