Metabotropic glutamate receptors belong to a family of G protein-coupled receptors that are obligate dimers and possess a large extracellular ligand-binding domain that is linked via a cysteine-rich domain to their 7-transmembrane domain¹. Upon activation, these receptors undergo a large conformational change to transmit the ligand binding signal from the extracellular ligand-binding domain to the G protein-coupling 7-transmembrane domain². In this manuscript, we propose a model for a sequential, multistep activation mechanism of metabotropic glutamate receptor subtype 5. We present a series of structures in lipid nanodiscs, from inactive to fully active, including agonist-bound intermediate states. Further, using bulk and single-molecule fluorescence imaging, we reveal distinct receptor conformations upon allosteric modulator and G protein binding.

代谢型谷氨酸受体属于 G 蛋白偶联受体家族，该受体是专性二聚体，具有大的胞外配体结合结构域，该结构域通过富含半胱氨酸的结构域与其 7 次跨膜结构域相连¹。激活后，这些受体经历较大的构象变化，将配体结合信号从胞外配体结合结构域传递至 G 蛋白偶联 7 跨膜结构域²。在这篇手稿中，我们提出了代谢型谷氨酸受体亚型 5 的顺序、多步激活机制的模型。我们提出了脂质纳米盘中的一系列结构，从非活性到完全活性，包括激动剂结合的中间态。此外，使用批量和单分子荧光成像，我们揭示了变构调节剂和 G 蛋白结合时的不同受体构象。