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 a low-density lipoprotein receptor class A (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. In the present study, we determine the cryo-electron microscopy structure of active-state human RXFP1, bound to a single-chain version of the endogenous agonist relaxin-2 and the heterotrimeric G_s protein. Evolutionary coupling analysis and structure-guided functional experiments reveal that RXFP1 signals through a mechanism of autoinhibition. Our results explain how an unusual GPCR family functions, providing a path to rational drug development targeting the relaxin receptors.

松弛素家族肽受体 1 (RXFP1) 是松弛素 2 的受体，松弛素 2 是生殖和心血管生理学的重要调节因子。RXFP1 是一种多结构域 G 蛋白偶联受体 (GPCR)，其胞外域由低密度脂蛋白 A 类受体 (LDLa) 模块和富含亮氨酸的重复序列组成。RXFP1 信号转导机制与其他 GPCR 明显不同，但人们对其仍知之甚少。在本研究中，我们确定了活性状态人 RXFP1 的冷冻电子显微镜结构，该结构与单链版本的内源激动剂松弛素 2 和异三聚体 G s 蛋白_结合。进化耦合分析和结构引导的功能实验表明，RXFP1 通过自抑制机制发出信号。我们的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。