Structural basis of orientated asymmetry in a mGlu heterodimer

Weizhu Huang, Nan Jin, Jia Guo, Cangsong Shen, Chanjuan Xu, Kun Xi, Léo Bonhomme, Robert B. Quast, Dan-Dan Shen, Jiao Qin, Yi-Ru Liu, Yuxuan Song, Yang Gao, Emmanuel Margeat, Philippe Rondard, Jean-Philippe Pin (), Yan Zhang () and Jianfeng Liu ()
Additional contact information
Weizhu Huang: Huazhong University of Science and Technology (HUST)
Nan Jin: Huazhong University of Science and Technology (HUST)
Jia Guo: Zhejiang University School of Medicine
Cangsong Shen: Huazhong University of Science and Technology (HUST)
Chanjuan Xu: Huazhong University of Science and Technology (HUST)
Kun Xi: Zhejiang University School of Medicine
Léo Bonhomme: Centre de Biologie Structurale (CBS), Univ. Montpellier, CNRS, INSERM
Robert B. Quast: Centre de Biologie Structurale (CBS), Univ. Montpellier, CNRS, INSERM
Dan-Dan Shen: Zhejiang University School of Medicine
Jiao Qin: Zhejiang University School of Medicine
Yi-Ru Liu: Huazhong University of Science and Technology (HUST)
Yuxuan Song: Huazhong University of Science and Technology (HUST)
Yang Gao: Zhejiang University
Emmanuel Margeat: Centre de Biologie Structurale (CBS), Univ. Montpellier, CNRS, INSERM
Philippe Rondard: Institut de Génomique Fonctionnelle (IGF), Univ. Montpellier, CNRS, INSERM
Jean-Philippe Pin: Institut de Génomique Fonctionnelle (IGF), Univ. Montpellier, CNRS, INSERM
Yan Zhang: Zhejiang University School of Medicine
Jianfeng Liu: Huazhong University of Science and Technology (HUST)

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract The structural basis for the allosteric interactions within G protein-coupled receptors (GPCRs) heterodimers remains largely unknown. The metabotropic glutamate (mGlu) receptors are complex dimeric GPCRs important for the fine tuning of many synapses. Heterodimeric mGlu receptors with specific allosteric properties have been identified in the brain. Here we report four cryo-electron microscopy structures of mGlu2-4 heterodimer in different states: an inactive state bound to antagonists, two intermediate states bound to either mGlu2 or mGlu4 agonist only and an active state bound to both glutamate and a mGlu4 positive allosteric modulator (PAM) in complex with Gi protein. In addition to revealing a unique PAM binding pocket among mGlu receptors, our data bring important information for the asymmetric activation of mGlu heterodimers. First, we show that agonist binding to a single subunit in the extracellular domain is not sufficient to stabilize an active dimer conformation. Single-molecule FRET data show that the monoliganded mGlu2-4 can be found in both intermediate states and an active one. Second, we provide a detailed view of the asymmetric interface in seven-transmembrane (7TM) domains and identified key residues within the mGlu2 7TM that limits its activation leaving mGlu4 as the only subunit activating G proteins.

Date: 2024
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DOI: 10.1038/s41467-024-54744-7

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