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Cryo-EM structure of Gi-bound metabotropic glutamate receptor mGlu4Cryo-EM structure of Gi-bound metabotropic glutamate receptor mGlu4
Structural highlights
FunctionGRM4_HUMAN G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling inhibits adenylate cyclase activity.[1] [2] [3] Publication Abstract from PubMedThe metabotropic glutamate receptors (mGlus) have key roles in modulating cell excitability and synaptic transmission in response to glutamate (the main excitatory neurotransmitter in the central nervous system)(1). It has previously been suggested that only one receptor subunit within an mGlu homodimer is responsible for coupling to G protein during receptor activation(2). However, the molecular mechanism that underlies the asymmetric signalling of mGlus remains unknown. Here we report two cryo-electron microscopy structures of human mGlu2 and mGlu4 bound to heterotrimeric Gi protein. The structures reveal a G-protein-binding site formed by three intracellular loops and helices III and IV that is distinct from the corresponding binding site in all of the other G-protein-coupled receptor (GPCR) structures. Furthermore, we observed an asymmetric dimer interface of the transmembrane domain of the receptor in the two mGlu-Gi structures. We confirmed that the asymmetric dimerization is crucial for receptor activation, which was supported by functional data; this dimerization may provide a molecular basis for the asymmetric signal transduction of mGlus. These findings offer insights into receptor signalling of class C GPCRs. Structures of Gi-bound metabotropic glutamate receptors mGlu2 and mGlu4.,Lin S, Han S, Cai X, Tan Q, Zhou K, Wang D, Wang X, Du J, Yi C, Chu X, Dai A, Zhou Y, Chen Y, Zhou Y, Liu H, Liu J, Yang D, Wang MW, Zhao Q, Wu B Nature. 2021 Jun;594(7864):583-588. doi: 10.1038/s41586-021-03495-2. Epub 2021, Jun 16. PMID:34135510[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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