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  Structures of active melanocortin-4 receptor−Gs-protein complexes with NDP-α-MSH and setmelanotide

Heyder, N. A., Kleinau, G., Speck, D., Schmidt, A., Paisdzior, S., Szczepek, M., et al. (2021). Structures of active melanocortin-4 receptor−Gs-protein complexes with NDP-α-MSH and setmelanotide. Cell Research, 0:1–14. doi:10.1038/s41422-021-00569-8.

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 Urheber:
Heyder, Nicolas A. , Autor
Kleinau, Gunnar , Autor
Speck, David, Autor
Schmidt, Andrea, Autor
Paisdzior, Sarah , Autor
Szczepek, Michal , Autor
Bauer, Brian, Autor
Koch, Anja, Autor
Gallandi, Monique , Autor
Kwiatkowski, Dennis , Autor
Bürger, Jörg1, Autor           
Mielke, Thorsten1, Autor           
Beck-Sickinger, Annette G. , Autor
Hildebrand, Peter W., Autor
Spahn, Christian M. T. , Autor
Hilger, Daniel, Autor
Schacherl, Magdalena , Autor
Biebermann, Heike, Autor
Hilal, Tarek, Autor
Kühnen, Peter, Autor
Kobilka, Brian K. , AutorScheerer, Patrick, Autor mehr..
Affiliations:
1Microscopy and Cryo-Electron Microscopy (Head: Thorsten Mielke), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479668              

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 Zusammenfassung: 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.

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Sprache(n): eng - English
 Datum: 2021-08-312021-09-24
 Publikationsstatus: Online veröffentlicht
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 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: -
 Identifikatoren: DOI: 10.1038/s41422-021-00569-8
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Titel: Cell Research
  Andere : Cell Res.
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: Beijing, China : Science Press
Seiten: - Band / Heft: - Artikelnummer: 0:1–14 Start- / Endseite: - Identifikator: ISSN: 1001-0602 (print) 1748-7838 (online)
CoNE: https://pure.mpg.de/cone/journals/resource/954927710256