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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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Heyder, Nicolas A. , Author
Kleinau, Gunnar , Author
Speck, David, Author
Schmidt, Andrea, Author
Paisdzior, Sarah , Author
Szczepek, Michal , Author
Bauer, Brian, Author
Koch, Anja, Author
Gallandi, Monique , Author
Kwiatkowski, Dennis , Author
Bürger, Jörg1, Author              
Mielke, Thorsten1, Author              
Beck-Sickinger, Annette G. , Author
Hildebrand, Peter W., Author
Spahn, Christian M. T. , Author
Hilger, Daniel, Author
Schacherl, Magdalena , Author
Biebermann, Heike, Author
Hilal, Tarek, Author
Kühnen, Peter, Author
Kobilka, Brian K. , AuthorScheerer, Patrick, Author more..
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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 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.

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Language(s): eng - English
 Dates: 2021-08-312021-09-24
 Publication Status: Published online
 Pages: -
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 Rev. Type: -
 Identifiers: DOI: 10.1038/s41422-021-00569-8
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Title: Cell Research
  Other : Cell Res.
Source Genre: Journal
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Publ. Info: Beijing, China : Science Press
Pages: - Volume / Issue: - Sequence Number: 0:1–14 Start / End Page: - Identifier: ISSN: 1001-0602 (print) 1748-7838 (online)
CoNE: https://pure.mpg.de/cone/journals/resource/954927710256