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CryoEM structure of mGlu6 captures receptor activation prior to G protein coupling
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CryoEM structure of mGlu6 captures receptor activation prior to G protein coupling
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Journal Article
CryoEM structure of mGlu6 captures receptor activation prior to G protein coupling
2026
Overview
The metabotropic glutamate receptor 6 (mGlu6) is essential for synaptic communication of rod photoreceptors, and mutations in mGlu6 lead to a blinding disorder. However, its structural organization remains unknown. Here, we present the structure of agonist-bound mGlu6, revealing an asymmetric dimer arrangement in the absence of a G protein. This indicates that agonist binding alone can induce the homodimeric receptor asymmetry in metabotropic glutamate receptors and structurally prime mGlu6 for activation by pre-organizing the transmembrane domain dimer interface for G protein binding. The structure also identifies noncanonical interactions between the cysteine-rich domain and extracellular loop 2, forming a unique interface that likely stabilizes the activation state. Mutational analyses of this interface reveal its role in maintaining rapid Gαo activation and surface targeting. The structure also permits mechanistic investigation of congenital stationary night blindness and reveals diverse effects of pathogenic mutations on surface trafficking, Gαo coupling, and activation dynamics, including unexpected gain-of-function. These results provide critical insight into the intermediate asymmetric structure of mGlu6 and offer a molecular framework for understanding the pathogenesis of inherited retinal disorders.
Metabotropic glutamate receptor 6 (mGlu6) mediates visual signaling in the retina. Here, authors report cryo-EM structures of mGlu6, providing structural insight into the asymmetric intermediate state and congenital stationary night blindness.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ Agonists
/ Animals
/ Binding
/ Coupling
/ Dimers
/ Glutamic acid receptors (metabotropic)
/ GTP-Binding Proteins - metabolism
/ Humanities and Social Sciences
/ Humans
/ Ligands
/ Mutation
/ Night
/ Night Blindness - metabolism
/ Proteins
/ Receptors, Metabotropic Glutamate - chemistry
/ Receptors, Metabotropic Glutamate - genetics
/ Receptors, Metabotropic Glutamate - metabolism
/ Receptors, Metabotropic Glutamate - ultrastructure
/ Science
/ Symmetry
