Volume 31, No 11, Nov 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 11, November 2021: 1176-1189   |  Open Access

ORIGINAL ARTICLES

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

Nicolas A. Heyder¹ , Gunnar Kleinau^1,† , David Speck^1,† , Andrea Schmidt^1,† , Sarah Paisdzior^2,† , Michal Szczepek¹ , Brian Bauer¹ , Anja Koch1¹ , Monique Gallandi¹ , Dennis Kwiatkowski¹ , Jörg Bürger^3,4 , Thorsten Mielke⁴ , Annette G. Beck-Sickinger⁵ , Peter W. Hildebrand^3,6,7 , Christian M. T. Spahn³ , Daniel Hilger⁸ , Magdalena Schacherl³ , Heike Biebermann² , Tarek Hilal⁹ , Peter Kühnen² , Brian K. Kobilka^7,10 , Patrick Scheerer^1,11,*

¹Charité – 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
²Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and HumboldtUniversität zu Berlin, Institute for Experimental Pediatric Endocrinology, Berlin, Germany
³Charité – Universitätsmedizin Berlin, Institute of Medical Physics and Biophysics, Berlin, Germany
⁴Microscopy and Cryo-Electron Microscopy Service Group, Max-Planck-Institut für Molekulare Genetik, Berlin, Germany
⁵Faculty of Life Sciences, Institute of Biochemistry, Leipzig University, Leipzig, Germany
⁶Institute for Medical Physics and Biophysics, Medical Faculty, Leipzig University, Leipzig, Germany
⁷Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Core Facility Genomics, Charitéplatz 1, Berlin, Germany
⁸Department of Pharmaceutical Chemistry, Philipps-University Marburg, Marburg, Germany
⁹Research Center of Electron Microscopy and Core Facility BioSupraMol, Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
¹⁰Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA
¹¹DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany
^†These authors contributed equally: Gunnar Kleinau, David Speck, Andrea Schmidt, Sarah Paisdzior
Correspondence: Patrick Scheerer(patrick.scheerer@charite.de)

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.

https://doi.org/10.1038/s41422-021-00569-8

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