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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
G protein selectivity in group I metabotropic glutamate receptors
Yue Lu1,2, Tianlei Wen1, Xuhang Lu3
1State Key Laboratory of Medicinal Chemical Biology and Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300350, China.
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 Gq/11, whereas group II and III receptors primarily engage Gi/o. Although Gi/o-coupling mechanisms have been defined for several group II/III receptors, how group I receptors preferentially engage Gq/11 remains unclear. Here we report cryo-electron microscopy structures of active mGlu-G protein complexes (mGlu1-Gq, mGlu1-Gi, mGlu5-Gq, and mGlu5-Gi) 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 Gq 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 W6.50 rotation and TM6 outward movement, bringing the two 7TMs into closer. These findings provide a structural basis for preferential Gq/11 engagement and activation of group I mGlu receptors.
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