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

  1. Lei Liu
  2. Zhiran Fan
  3. Xavier Rovira  Is a corresponding author
  4. Li Xue
  5. Salomé Roux
  6. Isabelle Brabet
  7. Mingxia Xin
  8. Jean-Philippe Pin  Is a corresponding author
  9. Philippe Rondard  Is a corresponding author
  10. Jianfeng Liu  Is a corresponding author
  1. Huazhong University of Science and Technology, China
  2. Spanish National Research Council, Spain
  3. 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.

Article and author information

Author details

  1. Lei Liu

    Cellular Signaling Laboratory, International Research Center for Sensory Biology and Technology of MOST, Huazhong University of Science and Technology, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9824-9570
  2. Zhiran Fan

    Cellular Signaling Laboratory, International Research Center for Sensory Biology and Technology of MOST, Huazhong University of Science and Technology, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9543-1211
  3. Xavier Rovira

    MCS, Laboratory of Medicinal Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Spanish National Research Council, Barcelona, Spain
    For correspondence
    xavier.rovira@cid.csic.es
    Competing interests
    The authors declare that no competing interests exist.
  4. Li Xue

    Cellular Signaling Laboratory, International Research Center for Sensory Biology and Technology of MOST, Huazhong University of Science and Technology, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Salomé Roux

    Institut de Génomique Fonctionnelle, University of Montpellier, CNRS, INSERM, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6106-4863
  6. Isabelle Brabet

    Institut de Génomique Fonctionnelle, University of Montpellier, CNRS, INSERM, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Mingxia Xin

    Cellular Signaling Laboratory, International Research Center for Sensory Biology and Technology of MOST, Huazhong University of Science and Technology, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Jean-Philippe Pin

    Institut de Génomique Fonctionnelle, University of Montpellier, CNRS, INSERM, Montpellier, France
    For correspondence
    jean-philippe.pin@igf.cnrs.fr
    Competing interests
    The authors declare that no competing interests exist.
  9. Philippe Rondard

    Institut de Génomique Fonctionnelle, University of Montpellier, CNRS, INSERM, Montpellier, France
    For correspondence
    philippe.rondard@igf.cnrs.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1134-2738
  10. Jianfeng Liu

    Cellular Signaling Laboratory, International Research Center for Sensory Biology and Technology of MOST, Huazhong University of Science and Technology, Wuhan, China
    For correspondence
    jfliu@mail.hust.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0284-8377

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.

Reviewing Editor

  1. Andrew C Kruse, Harvard Medical School, United States

Publication history

  1. Received: May 9, 2021
  2. Accepted: December 2, 2021
  3. Accepted Manuscript published: December 6, 2021 (version 1)
  4. Accepted Manuscript updated: December 10, 2021 (version 2)
  5. Version of Record published: December 23, 2021 (version 3)

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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  1. Lei Liu
  2. Zhiran Fan
  3. Xavier Rovira
  4. Li Xue
  5. Salomé Roux
  6. Isabelle Brabet
  7. Mingxia Xin
  8. Jean-Philippe Pin
  9. Philippe Rondard
  10. Jianfeng Liu
(2021)
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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