PT-141 - 10mg
Structural insights into ligand recognition and activation of the melanocortin-4 receptor.
Huibing Zhang, Li-Nan Chen, Dehua Yang, Chunyou Mao, Qingya Shen, Wenbo Feng, Dan-Dan Shen, Antao Dai, Shanshan Xie, Yan Zhou, Jiao Qin, Jin-Peng Sun, Daniel H Scharf, Tingjun Hou, Tianhua Zhou, Ming-Wei Wang, Yan Zhang · 2022
Source abstract
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.