The relaxin family peptide receptor 1 (RXFP1) is the receptor for relaxin-2, an important regulator of reproductive and cardiovascular physiology. RXFP1 is a multi-domain G protein-coupled receptor (GPCR) with an ectodomain consisting of an LDLa module and leucine-rich repeats. The mechanism of RXFP1 signal transduction is clearly distinct from that of other GPCRs, but remains very poorly understood. Here, we present the cryo-electron microscopy structure of active-state human RXFP1, bound to a single-chain version of the endogenous agonist relaxin-2 and to the heterotrimeric Gs protein. Evolutionary coupling analysis and structure-guided functional experiments reveal that RXFP1 signals through a mechanism of autoinhibition, wherein the receptor's extracellular loop 2 occupies the orthosteric site in the active state but is inhibited by the ectodomain in the absence of relaxin-2. Our results explain how an unusual GPCR family functions, providing a path to rational drug development targeting the relaxin receptors.

中文翻译：

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松弛素受体 RXFP1 通过自身抑制机制发出信号

松弛素家族肽受体 1 (RXFP1) 是松弛素 2 的受体，松弛素是生殖和心血管生理学的重要调节剂。RXFP1 是一种多域 G 蛋白偶联受体 (GPCR)，其胞外域由 LDLa 模块和富含亮氨酸的重复序列组成。RXFP1 信号转导的机制明显不同于其他 GPCR，但仍知之甚少。在这里，我们展示了活跃状态的人 RXFP1 的低温电子显微镜结构，与内源性激动剂松弛素-2 的单链版本和异源三聚体 Gs 蛋白结合。进化耦合分析和结构引导的功能实验表明，RXFP1 通过自身抑制机制发出信号，其中受体' s 细胞外环 2 在活动状态下占据正构位点，但在没有松弛素 2 的情况下被胞外域抑制。我们的研究结果解释了一个不寻常的 GPCR 家族如何发挥作用，为针对松弛素受体的合理药物开发提供了一条途径。