Structures of human mGlu2 and mGlu7 homo- and heterodimers
Structures of human mGlu2 and mGlu7 homo- and heterodimers
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DOI：
10.1038/s41586-021-03641-w
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发表时间：
2021-06-16
期刊：
影响因子：
64.8
通讯作者：
Zhao, Qiang
中科院分区：
文献类型：
--
作者：
Du, Juan;Wang, Dejian;Zhao, Qiang
代谢型谷氨酸受体（mGlus）参与中枢神经系统中突触传递和神经元兴奋性的调节1。这些受体可能以同源和异源二聚体的形式存在，具有独特的药理学和功能特性（2-4）。在这里，我们报告四个冷冻电镜结构的人mGlu亚型mGlu 2和mGlu 7，包括无活性mGlu 2和mGlu 7同源二聚体; mGlu 2同源二聚体结合的激动剂和积极的变构调节剂;和无活性mGlu 2-mGlu 7异源二聚体。我们观察到这些mGlus的亚型依赖性二聚化模式，因为由螺旋IV介导的独特二聚体界面（并且对于限制受体活性很重要）仅存在于无活性mGlu 2结构中。这些结构提供了受体活化所需的亚基间和亚基内构象变化的分子细节，这将C类G蛋白偶联受体与A类和B类中的那些区分开来。此外，我们的mGlu 2-mGlu 7异二聚体的结构和功能的研究表明，mGlu 7亚基在控制二聚体的关联和G-蛋白激活的异二聚体中具有主导作用。这些对mGlu同二聚体和异二聚体的见解突出了mGlu二聚化和激活的复杂景观。
The metabotropic glutamate receptors (mGlus) are involved in the modulation of synaptic transmission and neuronal excitability in the central nervous system1. These receptors probably exist as both homo- and heterodimers that have unique pharmacological and functional properties(2-4). Here we report four cryo-electron microscopy structures of the human mGlu subtypes mGlu2 and mGlu7, including inactive mGlu2 and mGlu7 homodimers; mGlu2 homodimer bound to an agonist and a positive allosteric modulator; and inactive mGlu2-mGlu7 heterodimer. We observed a subtype-dependent dimerization mode for these mGlus, as a unique dimer interface that is mediated by helix IV (and that is important for limiting receptor activity) exists only in the inactive mGlu2 structure. The structures provide molecular details of the inter- and intra-subunit conformational changes that are required for receptor activation, which distinguish class C G-protein-coupled receptors from those in classes A and B. Furthermore, our structure and functional studies of the mGlu2-mGlu7 heterodimer suggest that the mGlu7 subunit has a dominant role in controlling dimeric association and G-protein activation in the heterodimer. These insights into mGlu homo- and heterodimers highlight the complex landscape of mGlu dimerization and activation.