Allosteric ligands control the activation of a class C GPCR heterodimer by acting at the transmembrane interface - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue eLife Année : 2021

Allosteric ligands control the activation of a class C GPCR heterodimer by acting at the transmembrane interface

Lei Liu
Zhiran Fan
Xavier Rovira
Connectez-vous pour contacter l'auteur
Li Xue
  • Fonction : Auteur
Salomé Roux
Isabelle Brabet
  • Fonction : Auteur
Mingxia Xin
  • Fonction : Auteur
Jean-Philippe Pin
Connectez-vous pour contacter l'auteur
Philippe Rondard
  • Fonction : Auteur correspondant
  • PersonId : 853446

Connectez-vous pour contacter l'auteur
Jianfeng Liu
  • Fonction : Auteur correspondant
  • PersonId : 853449

Connectez-vous pour contacter l'auteur

Résumé

G protein-coupled receptors (GPCRs) are among the most promising drug targets. They often form homo- and heterodimers with allosteric cross-talk between receptor entities, which contributes to fine-tuning of transmembrane signaling. Specifically controlling the activity of GPCR dimers with ligands is a good approach to clarify their physiological roles and validate them as drug targets. Here, we examined the mode of action of positive allosteric modulators (PAMs) that bind at the interface of the transmembrane domains of the heterodimeric GABAB receptor. Our site-directed mutagenesis results show that mutations of this interface impact the function of the three PAMs tested. The data support the inference that they act at the active interface between both transmembrane domains, the binding site involving residues of the TM6s of the GABAB1 and the GABAB2 subunit. Importantly, the agonist activity of these PAMs involves a key region in the central core of the GABAB2 transmembrane domain, which also controls the constitutive activity of the GABAB receptor. This region corresponds to the sodium ion binding site in class A GPCRs that controls the basal state of the receptors. Overall, these data reveal the possibility of developing allosteric compounds able to specifically modulate the activity of GPCR homo- and heterodimers by acting at their transmembrane interface.
Fichier principal
Vignette du fichier
Liu GABAB PAMs elife21.pdf (7.05 Mo) Télécharger le fichier
Origine Fichiers éditeurs autorisés sur une archive ouverte

Dates et versions

hal-03738955 , version 1 (27-07-2022)

Identifiants

Citer

Lei Liu, Zhiran Fan, Xavier Rovira, Li Xue, Salomé Roux, et al.. Allosteric ligands control the activation of a class C GPCR heterodimer by acting at the transmembrane interface. eLife, 2021, 10, pp.e70188. ⟨10.7554/eLife.70188⟩. ⟨hal-03738955⟩

Collections

INSERM FRM
19 Consultations
11 Téléchargements

Altmetric

Partager

Gmail Mastodon Facebook X LinkedIn More