G 蛋白偶联受体通过 TM5-TM6 开关来调控 G 蛋白和 Gs 蛋白的选择性，这一现象已被血清素受体的结构所揭示。
GPCRs steer G and G selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors.
机构信息
The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
出版信息
Mol Cell. 2022 Jul 21;82(14):2681-2695.e6. doi: 10.1016/j.molcel.2022.05.031. Epub 2022 Jun 16.
Serotonin (or 5-hydroxytryptamine, 5-HT) is an important neurotransmitter that activates 12 different G protein-coupled receptors (GPCRs) through selective coupling of G, G or G proteins. The structural basis for G protein subtype selectivity by these GPCRs remains elusive. Here, we report the structures of the serotonin receptors 5-HT, 5-HT, and 5-HT with G, and 5-HT with G. The structures reveal that transmembrane helices TM5 and TM6 alternate lengths as a macro-switch to determine receptor's selectivity for G and G, 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 G or G. Together, these results present a common mechanism of G versus G protein coupling selectivity or promiscuity by class A GPCRs and extend the basis of ligand recognition at serotonin receptors.
血清素（或 5-羟色胺，5-HT）是一种重要的神经递质，通过 G、G 或 G 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不清楚。在这里，我们报告了血清素受体 5-HT、5-HT 和 5-HT 与 G、5-HT 与 G 的结构。这些结构表明，跨膜螺旋 TM5 和 TM6 的长度交替作为一个宏观开关，分别决定受体对 G 和 G 的选择性。我们发现，TM5-TM6 长度的宏观开关在 A 类 GPCR-G 蛋白结构中是共享的。此外，我们发现 TM5 和 TM6 内的特定残基作为微开关，与 G 或 G 形成特定的相互作用。总之，这些结果提出了 A 类 GPCR 介导的 G 蛋白与 G 蛋白偶联选择性或混杂性的共同机制，并扩展了血清素受体中配体识别的基础。
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