Krishna Kumar Kaavya, Wang Haoqing, Habrian Chris, Latorraca Naomi R, Xu Jun, O'Brien Evan S, Zhang Chensong, Montabana Elizabeth, Koehl Antoine, Marqusee Susan, Isacoff Ehud Y, Kobilka Brian K
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
Nature. 2024 May;629(8013):951-956. doi: 10.1038/s41586-024-07327-x. Epub 2024 Apr 17.
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 domain. 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 domain. 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，是 obligate 二聚体，具有一个大的细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它们的7跨膜结构域相连。激活后，这些受体经历大的构象变化，将配体结合信号从细胞外配体结合结构域传递到G蛋白偶联的7跨膜结构域。在本手稿中，我们提出了一个代谢型谷氨酸受体亚型5的顺序多步激活机制模型。我们展示了一系列在脂质纳米盘中从无活性到完全活性的结构，包括激动剂结合的中间状态。此外，使用整体和单分子荧光成像，我们揭示了变构调节剂和G蛋白结合后不同的受体构象。
