【摘 要】
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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
【机 构】
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Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital,Zhejiang Universit
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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 Gs protein stimulated by the endogenous peptide ligand α-MSH,FDA-approved drugs afamelanotide (ScenesseTM) and bremelanotide (VyleesiTM),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.
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