Stimulation of the metabotropic GABAB receptor by γ-aminobutyric acid (GABA) results in prolonged inhibition of neurotransmission, which is central to brain physiology1. GABAB belongs to family C of the G-protein-coupled receptors, which operate as dimers to transform synaptic neurotransmitter signals into a cellular response through the binding and activation of heterotrimeric G proteins2,3. However, GABAB is unique in its function as an obligate heterodimer in which agonist binding and G-protein activation take place on distinct subunits4,5. Here we present cryo-electron microscopy structures of heterodimeric and homodimeric full-length GABAB receptors. Complemented by cellular signalling assays and atomistic simulations, these structures reveal that extracellular loop 2 (ECL2) of GABAB has an essential role in relaying structural transitions by ordering the linker that connects the extracellular ligand-binding domain to the transmembrane region. Furthermore, the ECL2 of each of the subunits of GABAB caps and interacts with the hydrophilic head of a phospholipid that occupies the extracellular half of the transmembrane domain, thereby providing a potentially crucial link between ligand binding and the receptor core that engages G proteins. These results provide a starting framework through which to decipher the mechanistic modes of signal transduction mediated by GABAB dimers, and have important implications for rational drug design that targets these receptors. Cryo-electron microscopy structures of heterodimeric and homodimeric full-length GABAB receptors, combined with cellular signalling assays, shed light on the mechanisms that underpin signal transduction mediated by these receptors.

中文翻译：

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代谢型 GABAB 受体的结构

γ-氨基丁酸 (GABA) 对代谢型 GABAB 受体的刺激导致神经传递的长期抑制，这是大脑生理学的核心1。GABAB 属于 G 蛋白偶联受体的 C 家族，其作为二聚体运作，通过异源三聚体 G 蛋白的结合和激活将突触神经递质信号转化为细胞反应2,3。然而，GABAB 的独特之处在于其作为专性异源二聚体的功能，其中激动剂结合和 G 蛋白激活发生在不同的亚基上 4,5。在这里，我们展示了异二聚体和同二聚体全长 GABAB 受体的冷冻电子显微镜结构。辅以细胞信号分析和原子模拟，这些结构表明，GABAB 的细胞外环 2 (ECL2) 通过对将细胞外配体结合结构域连接到跨膜区的接头进行排序，在传递结构转变方面具有重要作用。此外，GABAB 的每个亚基的 ECL2 覆盖并与占据跨膜结构域胞外一半的磷脂的亲水头相互作用，从而在配体结合和与 G 蛋白结合的受体核心之间提供潜在的关键联系。这些结果提供了一个起始框架，通过该框架破译 GABAB 二聚体介导的信号转导机制模式，并对靶向这些受体的合理药物设计具有重要意义。异二聚体和同二聚体全长 GABAB 受体的冷冻电子显微镜结构，