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Structures of active melanocortin-4 receptor-Gs-protein complexes with NDP-α-MSH and setmelanotide.
Heyder, Nicolas A; Kleinau, Gunnar; Speck, David; Schmidt, Andrea; Paisdzior, Sarah; Szczepek, Michal; Bauer, Brian; Koch, Anja; Gallandi, Monique; Kwiatkowski, Dennis; Bürger, Jörg; Mielke, Thorsten; Beck-Sickinger, Annette G; Hildebrand, Peter W; Spahn, Christian M T; Hilger, Daniel; Schacherl, Magdalena; Biebermann, Heike; Hilal, Tarek; Kühnen, Peter; Kobilka, Brian K; Scheerer, Patrick.
Afiliación
  • Heyder NA; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Group Protein X-ray Crystallography and Signal Transduction, Charitéplatz 1, Berlin, Germany.
  • Kleinau G; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Group Protein X-ray Crystallography and Signal Transduction, Charitéplatz 1, Berlin, Germany.
  • Speck D; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Group Protein X-ray Crystallography and Signal Transduction, Charitéplatz 1, Berlin, Germany.
  • Schmidt A; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Group Protein X-ray Crystallography and Signal Transduction, Charitéplatz 1, Berlin, Germany.
  • Paisdzior S; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute for Experimental Pediatric Endocrinology, Berlin, Germany.
  • Szczepek M; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Group Protein X-ray Crystallography and Signal Transduction, Charitéplatz 1, Berlin, Germany.
  • Bauer B; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Group Protein X-ray Crystallography and Signal Transduction, Charitéplatz 1, Berlin, Germany.
  • Koch A; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Group Protein X-ray Crystallography and Signal Transduction, Charitéplatz 1, Berlin, Germany.
  • Gallandi M; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Group Protein X-ray Crystallography and Signal Transduction, Charitéplatz 1, Berlin, Germany.
  • Kwiatkowski D; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Group Protein X-ray Crystallography and Signal Transduction, Charitéplatz 1, Berlin, Germany.
  • Bürger J; Charité - Universitätsmedizin Berlin, Institute of Medical Physics and Biophysics, Berlin, Germany.
  • Mielke T; Microscopy and Cryo-Electron Microscopy Service Group, Max-Planck-Institut für Molekulare Genetik, Berlin, Germany.
  • Beck-Sickinger AG; Microscopy and Cryo-Electron Microscopy Service Group, Max-Planck-Institut für Molekulare Genetik, Berlin, Germany.
  • Hildebrand PW; Faculty of Life Sciences, Institute of Biochemistry, Leipzig University, Leipzig, Germany.
  • Spahn CMT; Charité - Universitätsmedizin Berlin, Institute of Medical Physics and Biophysics, Berlin, Germany.
  • Hilger D; Institute for Medical Physics and Biophysics, Medical Faculty, Leipzig University, Leipzig, Germany.
  • Schacherl M; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Core Facility Genomics, Charitéplatz 1, Berlin, Germany.
  • Biebermann H; Charité - Universitätsmedizin Berlin, Institute of Medical Physics and Biophysics, Berlin, Germany.
  • Hilal T; Department of Pharmaceutical Chemistry, Philipps-University Marburg, Marburg, Germany.
  • Kühnen P; Charité - Universitätsmedizin Berlin, Institute of Medical Physics and Biophysics, Berlin, Germany.
  • Kobilka BK; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute for Experimental Pediatric Endocrinology, Berlin, Germany.
  • Scheerer P; Research Center of Electron Microscopy and Core Facility BioSupraMol, Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.
Cell Res ; 31(11): 1176-1189, 2021 11.
Article en En | MEDLINE | ID: mdl-34561620
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Alfa-MSH / Receptor de Melanocortina Tipo 4 Idioma: En Revista: Cell Res Año: 2021 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Alfa-MSH / Receptor de Melanocortina Tipo 4 Idioma: En Revista: Cell Res Año: 2021 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido