Structures of Gi-bound metabotropic glutamate receptors mGlu2 and mGlu4

• Published in: Nature (London) 2021-06, Vol.594 (7864), p.583-588
• Main Authors: Lin, Shuling, Han, Shuo, Cai, Xiaoqing, Tan, Qiuxiang, Zhou, Kexiu, Wang, Dejian, Wang, Xinwei, Du, Juan, Yi, Cuiying, Chu, Xiaojing, Dai, Antao, Zhou, Yan, Chen, Yan, Zhou, Yu, Liu, Hong, Liu, Jianfeng, Yang, Dehua, Wang, Ming-Wei, Zhao, Qiang, Wu, Beili
• Format: Article
• Language: English
• Subjects: 101/28; 13/1; 13/109; 13/95; 631/45/535/1258/1259; 631/45/612/194; 82/16; 82/80; 82/83; 96/34; Asymmetry; Binding sites; Central nervous system; Coupling (molecular); Dimerization; Dimers; Electron microscopy; Excitability; G protein-coupled receptors; Glutamate receptors; Glutamic acid receptors (metabotropic); Helices; Humanities and Social Sciences; Microscopy; multidisciplinary; Neurotransmitters; Proteins; Receptor mechanisms; Receptors; Science; Science (multidisciplinary); Signal transduction; Signaling; Synaptic transmission
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-021-03495-2

The metabotropic glutamate receptors (mGlus) have key roles in modulating cell excitability and synaptic transmission in response to glutamate (the main excitatory neurotransmitter in the central nervous system) 1 . It has previously been suggested that only one receptor subunit within an mGlu homodimer is responsible for coupling to G protein during receptor activation 2 . However, the molecular mechanism that underlies the asymmetric signalling of mGlus remains unknown. Here we report two cryo-electron microscopy structures of human mGlu2 and mGlu4 bound to heterotrimeric G i protein. The structures reveal a G-protein-binding site formed by three intracellular loops and helices III and IV that is distinct from the corresponding binding site in all of the other G-protein-coupled receptor (GPCR) structures. Furthermore, we observed an asymmetric dimer interface of the transmembrane domain of the receptor in the two mGlu–G i structures. We confirmed that the asymmetric dimerization is crucial for receptor activation, which was supported by functional data; this dimerization may provide a molecular basis for the asymmetric signal transduction of mGlus. These findings offer insights into receptor signalling of class C GPCRs. Cryo-electron microscopy structures of mGlu2 and mGlu4 bound to heterotrimeric G i protein shed light on the molecular basis of asymmetric signal transduction by metabotropic glutamate receptors.