You Chongzhao, Zhang Yumu, Xu Peiyu, Huang Sijie, Yin Wanchao, Eric Xu H, Jiang Yi
The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Nat Commun. 2022 Apr 19;13(1):2045. doi: 10.1038/s41467-022-29683-w.
Neuromedin U receptors (NMURs), including NMUR1 and NMUR2, are a group of G-coupled G protein-coupled receptors (GPCRs). NMUR1 and NMUR2 play distinct, pleiotropic physiological functions in peripheral tissues and in the central nervous system (CNS), respectively, according to their distinct tissue distributions. These receptors are stimulated by two endogenous neuropeptides, neuromedin U and S (NMU and NMS) with similar binding affinities. NMURs have gathered attention as potential drug targets for obesity and inflammatory disorders. Specifically, selective agonists for NMUR2 in peripheral tissue show promising long-term anti-obesity effects with fewer CNS-related side effects. However, the mechanisms of peptide binding specificity and receptor activation remain elusive. Here, we report four cryo-electron microscopy structures of G chimera-coupled NMUR1 and NMUR2 in complexes with NMU and NMS. These structures reveal the conserved overall peptide-binding mode and the mechanism of peptide selectivity for specific NMURs, as well as the common activation mechanism of the NMUR subfamily. Together, these findings provide insights into the molecular basis of the peptide recognition and offer an opportunity for the design of the selective drugs targeting NMURs.
神经介素U受体（NMURs），包括NMUR1和NMUR2，是一组G蛋白偶联受体（GPCRs）。根据其不同的组织分布，NMUR1和NMUR2分别在周围组织和中枢神经系统（CNS）中发挥不同的、多效性的生理功能。这两种受体可被两种具有相似结合亲和力的内源性神经肽——神经介素U和S（NMU和NMS）激活。NMURs作为肥胖症和炎症性疾病的潜在药物靶点已受到关注。具体而言，外周组织中NMUR2的选择性激动剂显示出有前景的长期抗肥胖作用，且中枢神经系统相关副作用较少。然而，肽结合特异性和受体激活的机制仍不清楚。在此，我们报道了与NMU和NMS形成复合物的G嵌合体偶联的NMUR1和NMUR2的四个冷冻电镜结构。这些结构揭示了保守的整体肽结合模式、肽对特定NMURs的选择性机制，以及NMUR亚家族的共同激活机制。总之，这些发现为肽识别的分子基础提供了见解，并为设计靶向NMURs的选择性药物提供了机会。
