Allosteric ligands control the activation of a class C GPCR heterodimer by acting at the transmembrane interface
- Huazhong University of Science and Technology, China
- Spanish National Research Council, Spain
- University of Montpellier, CNRS, INSERM, France
Abstract
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 to 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 PAM 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.
Data availability
Figure 2- Source Data 1 contain the numerical data used to generate the figures;Figure 3 - Source Data 1 contain the numerical data used to generate the figures;Figure 4 - Source Data 1 contain the numerical data used to generate the figures;Figure 5 - Source Data 1 contain the numerical data used to generate the figures.
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Funding
Ministry of Science and Technology of the People's Republic of China (2018YFA0507003)
- Jianfeng Liu
Agence Nationale de la Recherche (ANR-09-PIRI-0011)
- Philippe Rondard
Fondation pour la recherche médicale FRM (FRM team: DEQ20170326522)
- Jean-Philippe Pin
Spanish Ministry of Economy (SAF2015-74132-JIN)
- Xavier Rovira
National Natural Science Foundation of China (81720108031)
- Jianfeng Liu
National Natural Science Foundation of China (81872945)
- Jianfeng Liu
National Natural Science Foundation of China (31721002)
- Jianfeng Liu
National Natural Science Foundation of China (31420103909)
- Jianfeng Liu
Ministry of Education of the People's Republic of China (B08029)
- Jianfeng Liu
Centre National de la Recherche Scientifique (PICS n{degree sign}07030)
- Philippe Rondard
Centre National de la Recherche Scientifique (PRC n{degree sign}1403)
- Philippe Rondard
Institut National de la Santé et de la Recherche Médicale (IRP Brain Signal)
- Philippe Rondard
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Liu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Allosteric ligands control the activation of a class C GPCR heterodimer by acting at the transmembrane interface
eLife 10:e70188.
https://doi.org/10.7554/eLife.70188
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