G-protein-coupled receptors (GPCRs) form the largest family of receptors encoded by the human genome (around 800 genes). They transduce signals by coupling to a small number of heterotrimeric G proteins (16 genes encoding different α-subunits). Each human cell contains several GPCRs and G proteins. The structural determinants of coupling of Gs to four different GPCRs have been elucidated1–4, but the molecular details of how the other G-protein classes couple to GPCRs are unknown. Here we present the cryo-electron microscopy structure of the serotonin 5-HT1B receptor (5-HT1BR) bound to the agonist donitriptan and coupled to an engineered Go heterotrimer. In this complex, 5-HT1BR is in an active state; the intracellular domain of the receptor is in a similar conformation to that observed for the β2-adrenoceptor (β2AR)3 or the adenosine A2A receptor (A2AR)1 in complex with Gs. In contrast to the complexes with Gs, the gap between the receptor and the Gβ-subunit in the Go–5-HT1BR complex precludes molecular contacts, and the interface between the Gα-subunit of Go and the receptor is considerably smaller. These differences are likely to be caused by the differences in the interactions with the C terminus of the Go α-subunit. The molecular variations between the interfaces of Go and Gs in complex with GPCRs may contribute substantially to both the specificity of coupling and the kinetics of signalling.The high-resolution structure of the serotonin 5-HT1B receptor in complex with the agonist donitriptan and a Go heterotrimer highlights features that may underlie the specificity of receptor–G-protein coupling and kinetics of signalling.

中文翻译：

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与异三聚体 Go 偶联的血清素 5-HT1B 受体的冷冻电镜结构

G 蛋白偶联受体 (GPCR) 构成了人类基因组编码的最大受体家族（大约 800 个基因）。它们通过与少量异源三聚体 G 蛋白（编码不同 α-亚基的 16 个基因）偶联来转导信号。每个人体细胞都包含几个 GPCR 和 G 蛋白。Gs 与四种不同 GPCR 偶联的结构决定因素已被阐明 1-4，但其他 G 蛋白类别如何与 GPCR 偶联的分子细节尚不清楚。在这里，我们展示了与激动剂多尼曲坦结合并与工程化 Go 异源三聚体偶联的血清素 5-HT1B 受体 (5-HT1BR) 的低温电子显微镜结构。在这个复合物中，5-HT1BR 处于活跃状态；受体的胞内结构域与在与 Gs 复合的 β2-肾上腺素受体 (β2AR)3 或腺苷 A2A 受体 (A2AR)1 中观察到的构象相似。与与 Gs 的复合物相比，Go-5-HT1BR 复合物中受体与 Gβ-亚基之间的间隙排除了分子接触，Go 的 Gα-亚基与受体之间的界面要小得多。这些差异很可能是由与 Go α-亚基的 C 末端相互作用的差异引起的。与 GPCR 复合的 Go 和 Gs 界面之间的分子变化可能对耦合的特异性和信号传导的动力学有很大贡献。