G protein selectivity in group I metabotropic glutamate receptors

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.