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GPCRs steer Gi and Gs selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors
Molecular Cell ( IF 16.0 ) Pub Date : 2022-06-16 , DOI: 10.1016/j.molcel.2022.05.031
Sijie Huang 1 , Peiyu Xu 2 , Dan-Dan Shen 3 , Icaro A Simon 4 , Chunyou Mao 3 , Yangxia Tan 1 , Huibing Zhang 3 , Kasper Harpsøe 5 , Huadong Li 1 , Yumu Zhang 1 , Chongzhao You 2 , Xuekui Yu 6 , Yi Jiang 2 , Yan Zhang 7 , David E Gloriam 5 , H Eric Xu 1
Affiliation  

Serotonin (or 5-hydroxytryptamine, 5-HT) is an important neurotransmitter that activates 12 different G protein-coupled receptors (GPCRs) through selective coupling of Gs, Gi, or Gq proteins. The structural basis for G protein subtype selectivity by these GPCRs remains elusive. Here, we report the structures of the serotonin receptors 5-HT4, 5-HT6, and 5-HT7 with Gs, and 5-HT4 with Gi1. The structures reveal that transmembrane helices TM5 and TM6 alternate lengths as a macro-switch to determine receptor’s selectivity for Gs and Gi, respectively. We find that the macro-switch by the TM5-TM6 length is shared by class A GPCR-G protein structures. Furthermore, we discover specific residues within TM5 and TM6 that function as micro-switches to form specific interactions with Gs or Gi. Together, these results present a common mechanism of Gs versus Gi protein coupling selectivity or promiscuity by class A GPCRs and extend the basis of ligand recognition at serotonin receptors.



中文翻译:

GPCRs 通过 TM5-TM6 开关控制 Gi 和 Gs 选择性,如血清素受体结构所揭示

5-羟色胺(或 5-羟色胺,5-HT)是一种重要的神经递质,可通过 G s、G i或 G q蛋白的选择性偶联激活 12 种不同的 G 蛋白偶联受体 (GPCR) 。这些 GPCR 对 G 蛋白亚型选择性的结构基础仍然难以捉摸。在这里,我们报告了血清素受体 5-HT 4、5-HT 6和 5-HT 7与 G s和 5-HT 4与 G i1的结构。这些结构表明跨膜螺旋 TM5 和 TM6 交替长度作为宏开关来确定受体对 G s和 G i的选择性, 分别。我们发现 TM5-TM6 长度的宏开关由 A 类 GPCR-G 蛋白结构共享。此外,我们发现了 TM5 和 TM6 中的特定残基,它们作为微开关与 G s或 G i形成特定的相互作用。总之,这些结果提出了 A 类 GPCR 对 G s与 G i蛋白偶联选择性或混杂的共同机制,并扩展了血清素受体上配体识别的基础。

更新日期:2022-06-16
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