G-protein activation by a metabotropic glutamate receptor

Article

关键词: ALLOSTERIC MODULATION;    HEPTAHELICAL DOMAIN;    MOLECULAR SWITCHES;    POTENT;    IDENTIFICATION;    DETERMINANTS;    ANTAGONIST;    DISCOVERY;    LIGANDS;    M1;   

DOI  :  10.1038/s41586-021-03680-3

来源: SCIE

【 摘 要 】

Family C G-protein-coupled receptors (GPCRs) operate as obligate dimers with extracellular domains that recognize small ligands, leading to G-protein activation on the transmembrane (TM) domains of these receptors by an unknown mechanism(1). Here we show structures of homodimers of the family C metabotropic glutamate receptor 2 (mGlu2) in distinct functional states and in complex with heterotrimeric G(i). Upon activation of the extracellular domain, the two transmembrane domains undergo extensive rearrangement in relative orientation to establish an asymmetric TM6-TM6 interface that promotes conformational changes in the cytoplasmic domain of one protomer. Nucleotide-bound G(i) can be observed pre-coupled to inactive mGlu2, but its transition to the nucleotide-free form seems to depend on establishing the active-state TM6-TM6 interface. In contrast to family A and B GPCRs, G-protein coupling does not involve the cytoplasmic opening of TM6 but is facilitated through the coordination of intracellular loops 2 and 3, as well as a critical contribution from the C terminus of the receptor. The findings highlight the synergy of global and local conformational transitions to facilitate a new mode of G-protein activation.

【 授权许可】

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