Structural insights into ligand recognition and activation of the melanocortin-4 receptor

• Published in: Cell research Vol. 31; no. 11; pp. 1163 - 1175
• Main Authors: Zhang, Huibing, Chen, Li-Nan, Yang, Dehua, Mao, Chunyou, Shen, Qingya, Feng, Wenbo, Shen, Dan-Dan, Dai, Antao, Xie, Shanshan, Zhou, Yan, Qin, Jiao, Sun, Jin-Peng, Scharf, Daniel H., Hou, Tingjun, Zhou, Tianhua, Wang, Ming-Wei, Zhang, Yan
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01.11.2021; Nature Publishing Group
• Subjects: 101/1; 101/28; 13/109; 13/95; 38/77; 45/70; 631/535/1258/1259; 631/80/86/2363; 82/80; 82/83; Agonists; Amino Acid Sequence; Biomedical and Life Sciences; Cell Biology; Chemical compounds; Coupling; Coupling (molecular); Drug development; Energy balance; Guanine nucleotide-binding protein; Homeostasis; Humans; Life Sciences; Ligands; Melanocortin; Melanocortin MC4 receptors; Obesity; Pharmacology; Proteins; Receptor, Melanocortin, Type 4 - chemistry; Receptors; Recognition; Selectivity
• ISSN: 1001-0602; 1748-7838; 1748-7838
• DOI: 10.1038/s41422-021-00552-3

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.