Role of stoichiometry in the dimer-stabilizing effect of AMPA receptor allosteric modulators.
ACS Chem Biol
; 9(1): 128-33, 2014 Jan 17.
Article
en En
| MEDLINE
| ID: mdl-24152170
ABSTRACT
Protein dimerization provides a mechanism for the modulation of cellular signaling events. In α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors, the rapidly desensitizing, activated state has been correlated with a weakly dimeric, glutamate-binding domain conformation. Allosteric modulators can form bridging interactions that stabilize the dimer interface. While most modulators can only bind to one position with a one modulator per dimer ratio, some thiazide-based modulators can bind to the interface in two symmetrical positions with a two modulator per dimer ratio. Based on small-angle X-ray scattering (SAXS) experiments, dimerization curves for the isolated glutamate-binding domain show that a second modulator binding site produces both an increase in positive cooperativity and a decrease in the EC50 for dimerization. Four body binding equilibrium models that incorporate a second dimer-stabilizing ligand were developed to fit the experimental data. The work illustrates why stoichiometry should be an important consideration during the rational design of dimerizing modulators.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Receptores AMPA
/
Regulación Alostérica
/
Tiazidas
/
Multimerización de Proteína
Límite:
Animals
Idioma:
En
Revista:
ACS Chem Biol
Año:
2014
Tipo del documento:
Article
País de afiliación:
Estados Unidos