Illuminating the activation mechanisms and allosteric properties of metabotropic glutamate receptors
Illuminating the activation mechanisms and allosteric properties of metabotropic glutamate receptors
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DOI：
10.1073/pnas.1215615110
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发表时间：
2013-04-09
影响因子：
11.1
通讯作者：
Rondard, Philippe
中科院分区：
文献类型：
--
作者：
Doumazane, Etienne;Scholler, Pauline;Rondard, Philippe
在多聚体细胞表面受体中，与受体活化相关的胞外配体结合结构域（ECD）的构象变化在很大程度上仍然未知。这是二聚体代谢型谷氨酸受体的情况，尽管已经解决了许多ECD结构。在这里，使用基于细胞表面标记和FRET的创新方法，我们证明了ECDs的重定向与受体和G蛋白激活相关。我们的方法有助于识别部分激动剂，并突出了效应器和结合结构域之间的变构相互作用。预期稳定效应结构域的活性构象的任何方法增加了稳定活性ECD构象的激动剂效力。这些数据提供了关于代谢型谷氨酸受体的结构动力学和药物作用的关键信息，并验证了用于处理其他受体的此类分析的方法。
In multimeric cell-surface receptors, the conformational changes of the extracellular ligand-binding domains (ECDs) associated with receptor activation remain largely unknown. This is the case for the dimeric metabotropic glutamate receptors even though a number of ECD structures have been solved. Here, using an innovative approach based on cell-surface labeling and FRET, we demonstrate that a reorientation of the ECDs is associated with receptor and G-protein activation. Our approach helps identify partial agonists and highlights allosteric interactions between the effector and binding domains. Any approach expected to stabilize the active conformation of the effector domain increased the agonist potency in stabilizing the active ECDs conformation. These data provide key information on the structural dynamics and drug action at metabotropic glutamate receptors and validate an approach for tackling such analysis on other receptors.