Jin Sanshan, Guo Shimeng, Xu Youwei, Li Xin, Wu Canrong, He Xinheng, Pan Benxun, Xin Wenwen, Zhang Heng, Hu Wen, Yin Yuling, Zhang Tianwei, Wu Kai, Yuan Qingning, Xu H Eric, Xie Xin, Jiang Yi
Lingang Laboratory, Shanghai, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Cell Discov. 2024 Jun 4;10(1):58. doi: 10.1038/s41421-024-00670-3.
The neuropeptide 26RFa, a member of the RF-amide peptide family, activates the pyroglutamylated RF-amide peptide receptor (QRFPR), a class A GPCR. The 26RFa/QRFPR system plays critical roles in energy homeostasis, making QRFPR an attractive drug target for treating obesity, diabetes, and eating disorders. However, the lack of structural information has hindered our understanding of the peptide recognition and regulatory mechanism of QRFPR, impeding drug design efforts. In this study, we determined the cryo-EM structure of the G-coupled QRFPR bound to 26RFa. The structure reveals a unique assembly mode of the extracellular region of the receptor and the N-terminus of the peptide, and elucidates the recognition mechanism of the C-terminal heptapeptide of 26RFa by the transmembrane binding pocket of QRFPR. The study also clarifies the similarities and distinctions in the binding pattern of the RF-amide moiety in five RF-amide peptides and the RY-amide segment in neuropeptide Y. These findings deepen our understanding of the RF-amide peptide recognition, aiding in the rational design of drugs targeting QRFPR and other RF-amide peptide receptors.
神经肽26RFa是RF-酰胺肽家族的一员，可激活焦谷氨酸化RF-酰胺肽受体（QRFPR），这是一种A类G蛋白偶联受体。26RFa/QRFPR系统在能量稳态中起关键作用，使QRFPR成为治疗肥胖症、糖尿病和饮食失调的有吸引力的药物靶点。然而，缺乏结构信息阻碍了我们对QRFPR的肽识别和调节机制的理解，妨碍了药物设计工作。在本研究中，我们确定了与26RFa结合的G偶联QRFPR的冷冻电镜结构。该结构揭示了受体细胞外区域和肽N端的独特组装模式，并阐明了QRFPR跨膜结合口袋对26RFa C端七肽的识别机制。该研究还阐明了五种RF-酰胺肽中RF-酰胺部分和神经肽Y中RY-酰胺片段结合模式的异同。这些发现加深了我们对RF-酰胺肽识别的理解，有助于合理设计靶向QRFPR和其他RF-酰胺肽受体的药物。
