Extracellular loop 2 of G protein-coupled olfactory receptors is critical for odorant recognition.
J Biol Chem
; 298(9): 102331, 2022 09.
Article
en En
| MEDLINE
| ID: mdl-35926708
ABSTRACT
G protein-coupled olfactory receptors (ORs) enable us to detect innumerous odorants. They are also ectopically expressed in nonolfactory tissues and emerging as attractive drug targets. ORs can be promiscuous or highly specific, which is part of a larger mechanism for odor discrimination. Here, we demonstrate that the OR extracellular loop 2 (ECL2) plays critical roles in OR promiscuity and specificity. Using site-directed mutagenesis and molecular modeling, we constructed 3D OR models in which ECL2 forms a lid over the orthosteric pocket. We demonstrate using molecular dynamics simulations that ECL2 controls the shape and volume of the odorant-binding pocket, maintains the pocket hydrophobicity, and acts as a gatekeeper of odorant binding. Therefore, we propose the interplay between the specific orthosteric pocket and the variable, less specific ECL2 controls OR specificity and promiscuity. Furthermore, the 3D models created here enabled virtual screening of new OR agonists and antagonists, which exhibited a 70% hit rate in cell assays. Our approach can potentially be generalized to structure-based ligand screening for other G protein-coupled receptors that lack high-resolution 3D structures.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Olfato
/
Receptores Odorantes
/
Odorantes
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
J Biol Chem
Año:
2022
Tipo del documento:
Article