G protein selectivity in group I metabotropic glutamate receptors.
basic_science · Level V
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- Record sourced from PubMed, PMID 42430471.
- Also identified by DOI 10.1126/sciadv.aee0044.
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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<sub>q/11</sub>, whereas group II and III receptors primarily engage G<sub>i/o</sub>. Although G<sub>i/o</sub>-coupling mechanisms have been defined for several group II/III receptors, how group I receptors preferentially engage G<sub>q/11</sub> remains unclear. Here we report cryo-electron microscopy structures of active mGlu-G protein complexes (mGlu1-G<sub>q</sub>, mGlu1-G<sub>i</sub>, mGlu5-G<sub>q</sub>, and mGlu5-G<sub>i</sub>) 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<sub>q</sub> 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<sup>6.50</sup> rotation and TM6 outward movement, bringing the two 7TMs into closer. These findings provide a structural basis for preferential G<sub>q/11</sub> engagement and activation of group I mGlu receptors.
Medical subject headings
- Receptors, Metabotropic Glutamate
- GTP-Binding Proteins