Structural basis of orientated asymmetry in a mGlu heterodimer

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.

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Publication Details

Journal
Nature Communications
Published
2024-11-28
DOI
https://doi.org/10.1038/s41467-024-54744-7
Citations
11
Primary Topic
Receptor Mechanisms and Signaling
Type
article
Field-Weighted Citation Impact
2.57

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article

Structural basis of orientated asymmetry in a mGlu heterodimer

Chanjuan Xu, Jia Guo, Nan Jin, Jean‐Philippe Pin et al.
11 citations
Nature Communications
Receptor Mechanisms and Signaling
2.57
article

Structural basis of orientated asymmetry in a mGlu heterodimer

Chanjuan Xu, Jia Guo, Nan Jin, Jean‐Philippe Pin, Emmanuel Margeat, Yuxuan Song, Weimin Huang, Yang Gao, Yi-Ru Liu, Philippe Rondard, Léo Bonhomme, Robert B. Quast, Jianfeng Liu, Yan Zhang, Kun Xi, Cangsong Shen, Dan-Dan Shen, Jiao Qin
article en
11 citations

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.

Nature CommunicationsVol. 15(1)
Centre National de la Recherche Scientifique (FR), Inserm (FR), Université de Montpellier (FR), Sir Run Run Shaw Hospital (CN), Centre de Biologie Structurale (FR), Guangzhou Regenerative Medicine and Health Guangdong Laboratory (CN), Zhejiang Lab (CN), Institut de Génomique Fonctionnelle (FR), Huazhong University of Science and Technology (CN), Zhejiang University (CN)
Agence Nationale de la Recherche, National Natural Science Foundation of China, Fondation pour la Recherche Médicale, Zhejiang University, Universität Leipzig
Openalex Percentile: Top 10%
Receptor Mechanisms and Signaling
2.57
DOIOpen Access PDFOpenAlex
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