The human GABAB receptor—a member of the class C family of G-protein-coupled receptors (GPCRs)—mediates inhibitory neurotransmission and has been implicated in epilepsy, pain and addiction1. A unique GPCR that is known to require heterodimerization for function2–6, the GABAB receptor has two subunits, GABAB1 and GABAB2, that are structurally homologous but perform distinct and complementary functions. GABAB1 recognizes orthosteric ligands7,8, while GABAB2 couples with G proteins9–14. Each subunit is characterized by an extracellular Venus flytrap (VFT) module, a descending peptide linker, a seven-helix transmembrane domain and a cytoplasmic tail15. Although the VFT heterodimer structure has been resolved16, the structure of the full-length receptor and its transmembrane signalling mechanism remain unknown. Here we present a near full-length structure of the GABAB receptor, captured in an inactive state by cryo-electron microscopy. Our structure reveals several ligands that preassociate with the receptor, including two large endogenous phospholipids that are embedded within the transmembrane domains to maintain receptor integrity and modulate receptor function. We also identify a previously unknown heterodimer interface between transmembrane helices 3 and 5 of both subunits, which serves as a signature of the inactive conformation. A unique ‘intersubunit latch’ within this transmembrane interface maintains the inactive state, and its disruption leads to constitutive receptor activity. The structure of the GABAB receptor in an inactive state reveals, amongst other features, a latch between the two subunits that locks the transmembrane domain interface, and the presence of large phospholipids that may modulate receptor function.

中文翻译：

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非活性状态下的人类 GABAB 受体的结构


人类 GABAB 受体是 G 蛋白偶联受体 (GPCR) C 类家族的成员，介导抑制性神经传递，与癫痫、疼痛和成瘾有关1。 GABAB 受体是一种独特的 GPCR，已知需要异二聚化才能实现功能 2-6，它有两个亚基：GABAB1 和 GABAB2，它们在结构上是同源的，但执行不同且互补的功能。 GABAB1 识别正位配体 7,8，而 GABAB2 与 G 蛋白偶联 9-14。每个亚基的特征是胞外捕蝇草 (VFT) 模块、下行肽接头、七螺旋跨膜结构域和细胞质尾部15。尽管VFT异二聚体结构已被解析16，但全长受体的结构及其跨膜信号传导机制仍然未知。在这里，我们展示了 GABAB 受体的近全长结构，通过冷冻电子显微镜在非活性状态下捕获。我们的结构揭示了与受体预结合的几种配体，包括嵌入跨膜结构域内的两种大的内源性磷脂，以维持受体完整性并调节受体功能。我们还鉴定了两个亚基的跨膜螺旋 3 和 5 之间的先前未知的异二聚体界面，该界面作为非活性构象的特征。该跨膜界面内独特的“亚基间闩锁”维持非活性状态，其破坏导致组成型受体活性。除其他特征外，非活性状态下的 GABAB 受体的结构揭示了两个亚基之间锁定跨膜结构域界面的闩锁，以及可能调节受体功能的大磷脂的存在。