Melanocortins are peptide hormones critical for stress response, energy homeostasis, inflammation, and skin pigmentation. Their functions are mediated by five G protein-coupled receptors (MC1R to 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 provide a conserved mechanism of calcium-mediated ligand recognition, specific mode of G protein coupling, and a universal activation pathway of melanocortin receptors.

中文翻译：

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人黑皮质素-1受体钙介导的激素识别和Gβ相互作用的结构机制

黑皮质素是对压力反应、能量稳态、炎症和皮肤色素沉着至关重要的肽激素。它们的功能由五种 G 蛋白偶联受体（MC1R 到 MC5R）介导，主要通过刺激性 G 蛋白 (Gs)。MC1R 是黑皮质素受体的创始成员，主要在黑素细胞中表达并参与黑素生成。MC1R 的功能障碍与黑色素瘤和皮肤癌的发展有关。在这里，我们展示了与内源性激素 α-MSH、市售药物阿法拉肽和合成激动剂 SHU9119 结合的 MC1R-Gs 复合物的三种冷冻电子显微镜结构。这些结构揭示了黑皮质素中保守的 HFRW 基序的正构结合口袋，以及钙离子在配体结合中的关键作用。它们还证明了不同配体之间不同活性的基础。此外，从这些结构中发现了 MC1R 和 Gβ 亚基之间意想不到的相互作用。总之，我们的结果提供了钙介导的配体识别的保守机制、G 蛋白偶联的特定模式和黑皮质素受体的通用激活途径。