The Nicotinic Acetylcholine Receptor and Its Pentameric Homologs: Toward an Allosteric Mechanism of Signal Transduction at the Atomic Level.
Annu Rev Biochem
; 93(1): 339-366, 2024 Aug.
Article
en En
| MEDLINE
| ID: mdl-38346274
ABSTRACT
The nicotinic acetylcholine receptor has served, since its biochemical identification in the 1970s, as a model of an allosteric ligand-gated ion channel mediating signal transition at the synapse. In recent years, the application of X-ray crystallography and high-resolution cryo-electron microscopy, together with molecular dynamic simulations of nicotinic receptors and homologs, have opened a new era in the understanding of channel gating by the neurotransmitter. They reveal, at atomic resolution, the diversity and flexibility of the multiple ligand-binding sites, including recently discovered allosteric modulatory sites distinct from the neurotransmitter orthosteric site, and the conformational dynamics of the activation process as a molecular switch linking these multiple sites. The model emerging from these studies paves the way for a new pharmacology based, first, upon the occurrence of an original mode of indirect allosteric modulation, distinct from a steric competition for a single and rigid binding site, and second, the design of drugs that specifically interact with privileged conformations of the receptor such as agonists, antagonists, and desensitizers. Research on nicotinic receptors is still at the forefront of understanding the mode of action of drugs on the nervous system.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Receptores Nicotínicos
/
Microscopía por Crioelectrón
/
Sitio Alostérico
/
Simulación de Dinámica Molecular
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Annu Rev Biochem
Año:
2024
Tipo del documento:
Article
País de afiliación:
Francia