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

eLife

Mingxia Xin¹  Jianfeng Liu¹  Zhiran Fan¹  Lei Liu²  Li Xue²  Isabelle Brabet³  Jean-Philippe Pin³  Salomé Roux³  Philippe Rondard³  Xavier Rovira⁴ 

[1]Cellular Signaling Laboratory, International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of MOE, and College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China

[2]Cellular Signaling Laboratory, International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of MOE, and College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China

[3]Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France

[4]Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France

[5]MCS, Laboratory of Medicinal Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain

关键词: oligomer;    allosteric modulator;    allosteric agonism;    G protein;    metabotropic glutamate receptor;    GABA-B;    Human;   

DOI  :  10.7554/eLife.70188

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY