Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
Nature. 2019 Feb;566(7742):79-84. doi: 10.1038/s41586-019-0881-4. Epub 2019 Jan 23.
Metabotropic glutamate receptors are family C G-protein-coupled receptors. They form obligate dimers and possess extracellular ligand-binding Venus flytrap domains, which are linked by cysteine-rich domains to their 7-transmembrane domains. Spectroscopic studies show that signalling is a dynamic process, in which large-scale conformational changes underlie the transmission of signals from the extracellular Venus flytraps to the G protein-coupling domains-the 7-transmembrane domains-in the membrane. Here, using a combination of X-ray crystallography, cryo-electron microscopy and signalling studies, we present a structural framework for the activation mechanism of metabotropic glutamate receptor subtype 5. Our results show that agonist binding at the Venus flytraps leads to a compaction of the intersubunit dimer interface, thereby bringing the cysteine-rich domains into close proximity. Interactions between the cysteine-rich domains and the second extracellular loops of the receptor enable the rigid-body repositioning of the 7-transmembrane domains, which come into contact with each other to initiate signalling.
代谢型谷氨酸受体属于 C 族 G 蛋白偶联受体。它们形成必需的二聚体,并具有细胞外配体结合的 Venus 捕蝇草结构域,该结构域通过富含半胱氨酸的结构域与跨膜结构域的 7 个跨膜结构域相连。光谱研究表明,信号转导是一个动态过程,在这个过程中,从细胞外 Venus 捕蝇草到膜内的 G 蛋白偶联结构域(7 个跨膜结构域)的信号传递是由大规模构象变化来支撑的。在这里,我们结合使用 X 射线晶体学、冷冻电镜和信号研究,为代谢型谷氨酸受体 5 亚型的激活机制提供了一个结构框架。我们的研究结果表明,配体在 Venus 捕蝇草上的结合导致了亚基间二聚体界面的紧缩,从而使富含半胱氨酸的结构域紧密靠近。富含半胱氨酸的结构域与受体的第二个细胞外环之间的相互作用使 7 个跨膜结构域能够进行刚性重定位,使它们相互接触以启动信号转导。