Allosteric activation of metabotropic glutamate receptor 5.
J Biomol Struct Dyn
; 38(9): 2624-2632, 2020 Jun.
Article
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| MEDLINE
| ID: mdl-31258022
ABSTRACT
Metabotropic glutamate receptor 5 (mGluR5) is a class C G protein-coupled receptor (GPCR) with both an extracellular ligand binding site and an allosteric intrahelical chamber located similarly to the orthosteric ligand binding site of Class A GPCRs. Ligands binding to this ancestral site of mGluR5 can act as positive (PAM), negative (NAM) or silent (SAM) allosteric modulators, and their medicinal chemistry optimization is notoriously difficult, as subtle structural changes may cause significant variation in activity and switch in the functional response. Here we present all atom molecular dynamics simulations of NAM, SAM and PAM complexes formed by closely related ligands and analyse the structural differences of the complexes. Several residues involved in the activation are identified and the formation of a continuous water channel in the active complex but not in the inactive ones is recognized. Our results suggest that the mechanism of mGluR5 activation is similar to that of class A GPCRs.Communicated by Ramaswamy H. Sarma.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Simulación de Dinámica Molecular
/
Receptor del Glutamato Metabotropico 5
Idioma:
En
Revista:
J Biomol Struct Dyn
Año:
2020
Tipo del documento:
Article
País de afiliación:
Hungria