美国斯坦福大学医学院Brian K. Kobilka和Kaavya Krishna Kumar共同合作，近期取得重要工作进展。他们研究揭示了代谢型谷氨酸受体的逐步激活机制。相关研究成果2024年4月17日在线发表于《自然》杂志上。

据介绍，代谢型谷氨酸受体属于G蛋白偶联受体家族，它们是二聚体，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其7跨膜结构域连接。激活后，这些受体发生大的构象变化，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7跨膜结构域。

研究人员提出了一个代谢型谷氨酸受体亚型5的顺序、多步骤激活机制的模型。研究人员在脂质纳米盘中呈现了一系列结构，从非活性到完全活性，包括激动剂结合的中间状态。

此外，研究人员利用大分子和单分子荧光成像，揭示了变构调节剂和G蛋白结合时受体的不同构象。

附：英文原文

Title: Stepwise activation of a metabotropic glutamate receptor

Author: Krishna Kumar, Kaavya, Wang, Haoqing, Habrian, Chris, Latorraca, Naomi R., Xu, Jun, OBrien, Evan S., Zhang, Chensong, Montabana, Elizabeth, Koehl, Antoine, Marqusee, Susan, Isacoff, Ehud Y., Kobilka, Brian K.

Issue&Volume: 2024-04-17

Abstract: 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.

DOI: 10.1038/s41586-024-07327-x

Source: https://www.nature.com/articles/s41586-024-07327-x