Dongguan Songshan Lake Central Hospital, Dongguan Third People's Hospital, The Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, Dongguan, Guangdong, 523326, China.
Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, 518172, Guangdong, China.
Commun Biol. 2024 Nov 30;7(1):1598. doi: 10.1038/s42003-024-07228-9.
Chemerin, a chemotactic adipokine, plays essential roles in adipogenesis and inflammation. Serum chemerin concentration is closely associated with obesity and metabolism disorders. The mature form of chemerin (residues 21-157) acts primarily through chemerin receptor 1 (CMKLR1) for transmembrane signaling. As a result, CMKLR1 serves as a promising target for therapeutic intervention of immunometabolic diseases such as diabetes and multiple sclerosis. Here, we present a high-resolution cryo-EM structure of CMKLR1-Gi signaling complex bound to biologically active full-length chemerin. The mature chemerin shows binding features distinct from its C-terminal nonapeptide including interaction with both the extracellular loops (ECLs) and the N-terminus of CMKLR1. Combining results from functional assays, our studies demonstrate that chemerin interacts with CMKLR1 in a "two-site" mode similar to chemokine-chemokine receptor interactions, but acting as a "reverse chemokine" by inserting its C-terminus instead of the N-terminus as in the case of chemokines into the transmembrane binding pocket of CMKLR1. These structural insights are expected to help develop synthetic analogs with therapeutic potential.
趋化素是一种趋化性脂肪因子，在脂肪生成和炎症中发挥重要作用。血清趋化素浓度与肥胖和代谢紊乱密切相关。成熟形式的趋化素（残基 21-157）主要通过趋化素受体 1（CMKLR1）进行跨膜信号转导。因此，CMKLR1 是治疗糖尿病和多发性硬化等免疫代谢疾病的有前途的靶点。在这里，我们展示了 CMKLR1-Gi 信号复合物与生物活性全长趋化素结合的高分辨率冷冻电镜结构。成熟的趋化素表现出与 C 端九肽不同的结合特征，包括与 CMKLR1 的细胞外环（ECL）和 N 端相互作用。结合功能测定结果，我们的研究表明，趋化素以类似于趋化因子-趋化因子受体相互作用的“双位点”模式与 CMKLR1 相互作用，但作为“反向趋化因子”，其 C 端而不是 N 端插入 CMKLR1 的跨膜结合口袋，就像趋化因子一样。这些结构见解有望帮助开发具有治疗潜力的合成类似物。
