当前位置: X-MOL 学术bioRxiv. Pharmacol. Toxicol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
The relaxin receptor RXFP1 signals through a mechanism of autoinhibition
bioRxiv - Pharmacology and Toxicology Pub Date : 2022-09-19 , DOI: 10.1101/2022.01.22.477343
Sarah C. Erlandson , Shaun Rawson , James Osei-Owusu , Kelly P. Brock , Xinyue Liu , Joao A. Paulo , Julian Mintseris , Steven P. Gygi , Debora S. Marks , Xiaojing Cong , Andrew C. Kruse

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:

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。
更新日期:2022-09-20
down
wechat
bug