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您的检索式：作者名="Patrick Scheerer"
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| 1 | Structures of active melanocortin-4 receptor-Gs-protein complexes with NDP-a-MSH and setmelanotide显示文摘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-a-MSH and setmelanotide,with 2.9 A and 2.6 A 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-a-MSH,a high-affinity linear variant of the endogenous agonist a-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. | Nicolas A.Heyder Gunnar Kleinau David Speck Andrea Schmidt Sarah Paisdzior Michal Szczepek Brian Bauer Anja Koch Monique Gallandi Dennis Kwiatkowski Jorg Burger Thorsten Mielke Annette G.Beck-Sickinger Peter W.Hildebrand Christian M.T.Spahn Daniel Hilger Magdalena Schacherl Heike Biebermann Tarek Hilal Peter Kuhnen Brian K.Kobilka Patrick Scheerer | 2021 | Cell Research2021，31，11： | 0 |
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