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 mechanism¹. 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.

C 族 G 蛋白偶联受体 (GPCR) 作为专性二聚体，具有识别小配体的胞外结构域，通过未知机制¹在这些受体的跨膜 (TM) 结构域上激活 G 蛋白。在这里，我们展示了 C 族代谢型谷氨酸受体 2 (mGlu2) 同源二聚体在不同功能状态下和与异源三聚体 G _i复合的结构。在激活细胞外结构域后，两个跨膜结构域在相对方向上发生广泛的重排，以建立不对称的 TM6-TM6 界面，促进一个原体的细胞质结构域的构象变化。核苷酸结合的 G _i可以观察到预耦合到非活性 mGlu2，但其向无核苷酸形式的转变似乎取决于建立活性状态 TM6-TM6 界面。与家族 A 和 B GPCR 相比，G 蛋白偶联不涉及 TM6 的细胞质开放，而是通过细胞内环 2 和 3 的协调以及受体 C 末端的关键贡献来促进。这些发现强调了全局和局部构象转变的协同作用，以促进一种新的 G 蛋白激活模式。