The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
University of Chinese Academy of Sciences, Beijing, China.
Cell Res. 2021 Oct;31(10):1061-1071. doi: 10.1038/s41422-021-00557-y. Epub 2021 Aug 27.
Melanocortins are peptide hormones critical for the regulation of stress response, energy homeostasis, inflammation, and skin pigmentation. Their functions are mediated by five G protein-coupled receptors (MC1R-MC5R), predominately through the stimulatory G protein (Gs). MC1R, the founding member of melanocortin receptors, is mainly expressed in melanocytes and is involved in melanogenesis. Dysfunction of MC1R is associated with the development of melanoma and skin cancer. Here we present three cryo-electron microscopy structures of the MC1R-Gs complexes bound to endogenous hormone α-MSH, a marketed drug afamelanotide, and a synthetic agonist SHU9119. These structures reveal the orthosteric binding pocket for the conserved HFRW motif among melanocortins and the crucial role of calcium ion in ligand binding. They also demonstrate the basis of differential activities among different ligands. In addition, unexpected interactions between MC1R and the Gβ subunit were discovered from these structures. Together, our results elucidate a conserved mechanism of calcium-mediated ligand recognition, a specific mode of G protein coupling, and a universal activation pathway of melanocortin receptors.
黑素细胞刺激素是调节应激反应、能量平衡、炎症和皮肤色素沉着的关键肽类激素。它们的功能通过五种 G 蛋白偶联受体（MC1R-MC5R）介导，主要通过刺激 G 蛋白（Gs）。MC1R 是黑素细胞刺激素受体的创始成员，主要表达于黑素细胞中，参与黑素生成。MC1R 功能障碍与黑色素瘤和皮肤癌的发生有关。本文报道了 MC1R-Gs 复合物与内源性激素 α-MSH、市售药物阿法美拉汀和合成激动剂 SHU9119 结合的三个冷冻电镜结构。这些结构揭示了黑素细胞刺激素中保守的 HFRW 基序的变构结合口袋，以及钙离子在配体结合中的关键作用。它们还阐明了不同配体之间差异活性的基础。此外，这些结构还发现了 MC1R 与 Gβ 亚基之间的意外相互作用。总之，我们的研究结果阐明了钙介导的配体识别的保守机制、G 蛋白偶联的特定模式以及黑素细胞刺激素受体的通用激活途径。
