γ-氨基丁酸受体
代谢受体
异三聚体G蛋白
信号转导
跨膜结构域
生物物理学
代谢型谷氨酸受体
G蛋白偶联受体
神经递质受体
细胞生物学
化学
受体
生物
G蛋白
生物化学
兴奋剂
作者
Makaía M. Papasergi-Scott,Michael J. Robertson,Alpay B. Seven,Ouliana Panova,Jesper Mosolff Mathiesen,Georgios Skiniotis
出处
期刊:Nature
[Springer Nature]
日期:2020-06-24
卷期号:584 (7820): 310-314
被引量:70
标识
DOI:10.1038/s41586-020-2469-4
摘要
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.
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