Li Yang, Yuan Qingning, He Xinheng, Zhang Yumu, You Chongzhao, Wu Canrong, Li Jingru, Xu H Eric, Zhao Li-Hua
State Key Laboratory of Drug Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
University of Chinese Academy of Sciences, Beijing, China.
Cell Discov. 2024 Sep 3;10(1):91. doi: 10.1038/s41421-024-00724-6.
Prolactin-releasing peptide (PrRP) is an RF-amide neuropeptide that binds and activates its cognate G protein-coupled receptor, prolactin-releasing peptide receptor (PrRPR), also known as GPR10. PrRP and PrRPR are highly conserved across mammals and involved in regulating a range of physiological processes, including stress response, appetite regulation, pain modulation, cardiovascular function, and potentially reproductive functions. Here we present cryo-electron microscopy structures of PrRP-bound PrRPR coupled to G or G heterotrimer, unveiling distinct molecular determinants underlying the specific recognition of the ligand's C-terminal RF-amide motif. We identify a conserved polar pocket that accommodates the C-terminal amide shared by RF-amide peptides. Structural comparison with neuropeptide Y receptors reveals both similarities and differences in engaging the essential RF/RY-amide motifs. Our findings demonstrate the general mechanism governing RF-amide motif recognition by PrRPR and RF-amide peptide receptors, and provide a foundation for elucidating activation mechanisms and developing selective drugs targeting this important peptide-receptor system.
催乳素释放肽（PrRP）是一种RF-酰胺神经肽，它能结合并激活其同源G蛋白偶联受体——催乳素释放肽受体（PrRPR），也称为GPR10。PrRP和PrRPR在哺乳动物中高度保守，并参与调节一系列生理过程，包括应激反应、食欲调节、疼痛调制、心血管功能以及潜在的生殖功能。在此，我们展示了与G或G异源三聚体偶联的结合PrRP的PrRPR的冷冻电镜结构，揭示了配体C端RF-酰胺基序特异性识别背后不同的分子决定因素。我们确定了一个保守的极性口袋，可容纳RF-酰胺肽共有的C端酰胺。与神经肽Y受体的结构比较揭示了在结合关键的RF/RY-酰胺基序方面的异同。我们的研究结果证明了PrRPR和RF-酰胺肽受体识别RF-酰胺基序的一般机制，并为阐明激活机制和开发针对这一重要肽-受体系统的选择性药物奠定了基础。
