Melanocortin-4 receptor (MC4R) plays a central role in the regulation of energy homeostasis. Its high sequence similarity to other MC receptor family members, low agonist selectivity and the lack of structural information concerning MC4R-specific activation have hampered the development of MC4R-seletive therapeutics to treat obesity. Here, we report four high-resolution structures of full-length MC4R in complex with the heterotrimeric G_s protein stimulated by the endogenous peptide ligand α-MSH, FDA-approved drugs afamelanotide (Scenesse™) and bremelanotide (Vyleesi™), and a selective small-molecule ligand THIQ, respectively. Together with pharmacological studies, our results reveal the conserved binding mode of peptidic agonists, the distinctive molecular details of small-molecule agonist recognition underlying receptor subtype selectivity, and a distinct activation mechanism for MC4R, thereby offering new insights into G protein coupling. Our work may facilitate the discovery of selective therapeutic agents targeting MC4R.

黑皮质素 4 受体 (MC4R) 在能量稳态的调节中起核心作用。它与其他 MC 受体家族成员的高度序列相似性、低激动剂选择性和缺乏有关 MC4R 特异性激活的结构信息阻碍了 MC4R 选择性治疗肥胖症的发展。_{在这里，我们报告了与异三聚体 G s}复合的全长 MC4R 的四种高分辨率结构分别由内源性肽配体 α-MSH、FDA 批准的药物 afamelanotide (Sceneesse™) 和 bremelanotide (Vyleesi™) 以及选择性小分子配体 THIQ 刺激的蛋白质。结合药理学研究，我们的结果揭示了肽激动剂的保守结合模式、受体亚型选择性下小分子激动剂识别的独特分子细节以及 MC4R 的独特激活机制，从而为 G 蛋白偶联提供了新的见解。我们的工作可能有助于发现靶向 MC4R 的选择性治疗剂。