Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain
Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain
复制标题
DOI：
10.1038/nature13396
复制
发表时间：
2014-07-30
期刊：
影响因子：
64.8
通讯作者：
Marshall, Fiona H.
中科院分区：
文献类型：
--
作者：
Dore, Andrew S.;Okrasa, Krzysztof;Marshall, Fiona H.
代谢型谷氨酸受体是对神经递质谷氨酸做出反应的 C 类 G 蛋白偶联受体。结构研究仅限于氨基末端胞外结构域，对跨膜信号转导结构域的了解很少。代谢型谷氨酸受体 5 作为治疗脆性 X 综合征、自闭症、抑郁症、焦虑症、成瘾和运动障碍的药物靶点引起了相当大的兴趣。在这里，我们报告了与负变构调节剂 mavoglurant 复合的人类受体跨膜结构域的晶体结构。该结构提供了对 C 类受体跨膜结构域结构的详细了解，包括跨膜结构域内变构结合位点的精确位置以及调节受体信号传导的关键微开关。该结构还为所有类别的 CG 蛋白偶联受体提供了模型，并可能有助于设计用于治疗脑部疾病的新型小分子药物。
Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate. Structural studies have been restricted to the amino-terminal extracellular domain, providing little understanding of the membrane-spanning signal transduction domain. Metabotropic glutamate receptor 5 is of considerable interest as a drug target in the treatment of fragile X syndrome, autism, depression, anxiety, addiction and movement disorders. Here we report the crystal structure of the transmembrane domain of the human receptor in complex with the negative allosteric modulator, mavoglurant. The structure provides detailed insight into the architecture of the transmembrane domain of class C receptors including the precise location of the allosteric binding site within the transmem-branedomain and key micro-switches which regulate receptor signalling. This structure also provides a model for all class CG-protein-coupled receptors and may aid in the design of new small-molecule drugs for the treatment of brain disorders.