小柯机器人

代谢型GABA B受体结构获解析
2020-06-28 11:56

近日,美国斯坦福大学医学院Georgios Skiniotis及其研究小组解析出代谢型GABAB受体的结构。该研究于2020年6月24日在线发表于国际学术期刊《自然》。

研究人员解析了异源二聚体和同源二聚体全长GABAB受体的结构。通过细胞信号分析和原子模拟的补充,该结构揭示了GABAB细胞外环2(ECL2)的关键作用,即将衔接区域通过细胞外配体结合域连接至跨膜区。此外,这两个GABAB亚基的ECL2都与占据跨膜结构域的细胞外一半的磷脂亲水头部结合并相互作用,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,可用于破译由GABAB二聚体介导的信号转导的机械模式,并对针对这些受体的药物设计具有重要意义。
 
据悉,GABA(γ-氨基丁酸)对代谢型GABAB受体的刺激导致神经传递的长期抑制,而神经传递对大脑生理至关重要。GABAB属于G蛋白偶联受体(GPCR)的C家族,其作为二聚体起作用,通过异源三聚G蛋白的结合和激活将突触神经递质信号传递到细胞反应中。然而,GABAB作为专门的异二聚体的功能是独特的,其中激动剂结合和G蛋白活化发生在不同的亚基上。
 
附:英文原文

Title: Structures of metabotropic GABA B receptor

Author: Makaa M. Papasergi-Scott, Michael J. Robertson, Alpay B. Seven, Ouliana Panova, Jesper M. Mathiesen, Georgios Skiniotis

Issue&Volume: 2020-06-24

Abstract: GABA (γ-aminobutyric acid) stimulation of the metabotropic GABAB receptor results in prolonged inhibition of neurotransmission that is central to brain physiology1. GABAB belongs to the Family C of G protein-coupled receptors (GPCRs), which operate as dimers to relay synaptic neurotransmitter signals into a cellular response through the binding and activation of heterotrimeric G proteins2,3. GABAB, however, 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 show structures of heterodimeric and homodimeric full-length GABAB receptors. Complemented by cellular signaling assays and atomistic simulations, the structures reveal an essential role for the GABAB extracellular loop 2 (ECL2) in relaying structural transitions by ordering the linker connecting the extracellular ligand-binding domain to the transmembrane region. Furthermore, the ECL2 of both GABAB subunits caps and interacts with the hydrophilic head of a phospholipid occupying the extracellular half of the transmembrane domain, thereby providing a potentially crucial link between ligand binding and the receptor core that engages G protein. These results provide a starting framework to decipher mechanistic modes of signal transduction mediated by GABAB dimers and have important implications for rational drug design targeting these receptors.

DOI: 10.1038/s41586-020-2469-4

Source: https://www.nature.com/articles/s41586-020-2469-4

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

分享到:

0