催乳素释放肽通过其 G 蛋白偶联受体识别和传递信号的分子机制。

IF 13 1区 生物学 Q1 CELL BIOLOGY Cell Discovery Pub Date : 2024-09-03 DOI:10.1038/s41421-024-00724-6
Yang Li, Qingning Yuan, Xinheng He, Yumu Zhang, Chongzhao You, Canrong Wu, Jingru Li, H Eric Xu, Li-Hua Zhao
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引用次数: 0

摘要

催乳素释放肽(PrRP)是一种射频酰胺神经肽,可结合并激活其同源的 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,参与调节一系列生理过程,包括应激反应、食欲调节、疼痛调节、心血管功能以及潜在的生殖功能。在这里,我们展示了与 Gq 或 Gi 异源三聚体偶联的 PrRP 结合的 PrRPR 的冷冻电子显微镜结构,揭示了特异性识别配体 C 端 RF-amide motif 的独特分子决定因素。我们发现了一个保守的极性口袋,可容纳 RF-amide 肽共有的 C 端酰胺。通过与神经肽 Y 受体的结构比较,我们发现了与 RF/RY-amide 重要基团结合的相似之处和不同之处。我们的研究结果证明了 PrRPR 和 RF-amide 肽受体识别 RF-amide 主题的一般机制,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。
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Molecular mechanism of prolactin-releasing peptide recognition and signaling via its G protein-coupled receptor.

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 Gq or Gi 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.

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来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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