Institute of Biochemistry, Faculty of Life Sciences, Leipzig University, Brüderstr. 34, 04103, Leipzig, Germany.
Chembiochem. 2023 Sep 15;24(18):e202300280. doi: 10.1002/cbic.202300280. Epub 2023 Aug 9.
The adipokine chemerin is the endogenous ligand of the chemokine-like receptor 1 (CMKLR1), a member of the family of G protein-coupled receptors (GPCRs). This protein ligand plays an important role in obesity and inflammatory processes. Stable receptor-ligand interactions are highly relevant for its different physiological effects such as the migration of immune cells towards sites of inflammation. Here, we demonstrate that negative charges in the CMKLR1 N terminus are involved in the formation of strong contacts with a specific positively charged patch at the surface of full-length chemerin, which is absent in the short nonapeptide agonist chemerin-9, thus explaining its reduced affinity. Using receptor chimera of G protein-coupled receptor 1 (GPR1) and CMKLR1, we were able to identify the residues of this interaction and its relevance for stable full-length chemerin binding. This could help to develop more potent ligands for the treatment of inflammation-related diseases.
脂肪因子趋化素是趋化素样受体 1（CMKLR1）的内源性配体，CMKLR1 是 G 蛋白偶联受体（GPCR）家族的成员。这种蛋白配体在肥胖和炎症过程中发挥着重要作用。稳定的受体-配体相互作用对于其不同的生理效应非常重要，例如免疫细胞向炎症部位的迁移。在这里，我们证明 CMKLR1 N 端的负电荷参与了与全长趋化素表面特定正电荷斑块的强相互作用，而在短九肽激动剂趋化素-9 中则不存在该正电荷斑块，从而解释了其亲和力降低的原因。使用 G 蛋白偶联受体 1（GPR1）和 CMKLR1 的受体嵌合体，我们能够确定这种相互作用的残基及其对稳定全长趋化素结合的相关性。这有助于开发更有效的炎症相关疾病治疗药物。
