Structural insights into the activation of metabotropic glutamate receptors

Article

关键词: POSITIVE ALLOSTERIC MODULATORS;    G-PROTEIN;    HEPTAHELICAL DOMAIN;    SUBTYPE 5;    DISCOVERY;    COOPERATIVITY;    PHARMACOLOGY;    DIMERIZATION;    ANTAGONIST;    REFINEMENT;   

DOI  :  10.1038/s41586-019-0881-4

来源: SCIE

【 摘 要 】

Metabotropic glutamate receptors are family C G-protein-coupled receptors. They form obligate dimers and possess extracellular ligand-binding Venus flytrap domains, which are linked by cysteine-rich domains to their 7-transmembrane domains. Spectroscopic studies show that signalling is a dynamic process, in which large-scale conformational changes underlie the transmission of signals from the extracellular Venus flytraps to the G protein-coupling domains-the 7-transmembrane domains-in the membrane. Here, using a combination of X-ray crystallography, cryo-electron microscopy and signalling studies, we present a structural framework for the activation mechanism of metabotropic glutamate receptor subtype 5. Our results show that agonist binding at the Venus flytraps leads to a compaction of the intersubunit dimer interface, thereby bringing the cysteine-rich domains into close proximity. Interactions between the cysteine-rich domains and the second extracellular loops of the receptor enable the rigid-body repositioning of the 7-transmembrane domains, which come into contact with each other to initiate signalling.

【 授权许可】

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