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• W3200203208 abstract "Abstract The melanocortin-4 receptor (MC4R), a hypothalamic master regulator of energy homeostasis and appetite, is a class A G-protein-coupled receptor and a prime target for the pharmacological treatment of obesity. Here, we present cryo-electron microscopy structures of MC4R–Gs-protein complexes with two drugs recently approved by the FDA, the peptide agonists NDP-α-MSH and setmelanotide, with 2.9 Å and 2.6 Å resolution. Together with signaling data from structure-derived MC4R mutants, the complex structures reveal the agonist-induced origin of transmembrane helix (TM) 6-regulated receptor activation. The ligand-binding modes of NDP-α-MSH, a high-affinity linear variant of the endogenous agonist α-MSH, and setmelanotide, a cyclic anti-obesity drug with biased signaling toward Gq/11, underline the key role of TM3 in ligand-specific interactions and of calcium ion as a ligand-adaptable cofactor. The agonist-specific TM3 interplay subsequently impacts receptor–Gs-protein interfaces at intracellular loop 2, which also regulates the G-protein coupling profile of this promiscuous receptor. Finally, our structures reveal mechanistic details of MC4R activation/inhibition, and provide important insights into the regulation of the receptor signaling profile which will facilitate the development of tailored anti-obesity drugs." @default.
• W3200203208 created "2021-09-27" @default.
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• W3200203208 date "2021-09-24" @default.
• W3200203208 modified "2023-10-15" @default.
• W3200203208 title "Structures of active melanocortin-4 receptor–Gs-protein complexes with NDP-α-MSH and setmelanotide" @default.
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• W3200203208 doi "https://doi.org/10.1038/s41422-021-00569-8" @default.
• W3200203208 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8563958" @default.
• W3200203208 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/34561620" @default.
• W3200203208 hasPublicationYear "2021" @default.
• W3200203208 type Work @default.
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