G protein selectivity in group I metabotropic glutamate receptors.

Authors

Yue Lu, Tianlei Wen, Xuhang Lu, Guimin Zhang, Tingting Meng, Tianjin Liu, Xinyan Wang, Yuequan Shen, Xue Yang

Published in

Science advances. Volume 12. Issue 28. Pages eaee0044. Jul 10, 2026. Epub Jul 10, 2026.

Abstract

Metabotropic glutamate (mGlu) receptors are class C G protein-coupled receptor involved in synaptic transmission and neurological disorders. Group I mGlu receptors (mGlu1 and mGlu5) predominantly couple to G_q/11, whereas group II and III receptors primarily engage G_i/o. Although G_i/o-coupling mechanisms have been defined for several group II/III receptors, how group I receptors preferentially engage G_q/11 remains unclear. Here we report cryo-electron microscopy structures of active mGlu-G protein complexes (mGlu1-G_q, mGlu1-G_i, mGlu5-G_q, and mGlu5-G_i) bound to l-glutamate and positive allosteric modulators (PAMs), together with two additional activated-state structures of mGlu1. Comparative structural and biochemical analyses identify a group I-specific ICL2 insertion that promotes preferential G_q engagement. Each receptor dimer asymmetrically binds one G protein heterotrimer via an intracellular pocket engaging the Gα amino-terminal helix. PAM binding to one 7TM domain induces W^6.50 rotation and TM6 outward movement, bringing the two 7TMs into closer. These findings provide a structural basis for preferential G_q/11 engagement and activation of group I mGlu receptors.

PMID:
42430471
Bibliographic data and abstract were imported from PubMed on 11 Jul 2026.

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