7PIU

Cryo-EM structure of the agonist setmelanotide bound to the active melanocortin-4 receptor (MC4R) in complex with the heterotrimeric Gs protein at 2.6 A resolution.

Summary for 7PIU

• Entry DOI: 10.2210/pdb7piu/pdb
• Related: 7PIV
• EMDB information: 13453 13454
• Descriptor: Melanocortin receptor 4, Setmelanotide (other names RM-493; BIM-22493; IRC-022493; Imcivree), Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, ... (8 entities in total)
• Functional Keywords: gpcr, melanocortin-4 receptor, melanocortin receptors, setmelanotide, ndp-alpha-msh, alpha-msh, antagonism, agonism, appetite regulation, anti-obesity treatment, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 144449.67

Authors

Heyder, N.A.,Schmidt, A.,Kleinau, G.,Hilal, T.,Scheerer, P. (deposition date: 2021-08-23, release date: 2021-11-17, Last modification date: 2024-11-13)

Primary citation

Heyder, N.A.,Kleinau, G.,Speck, D.,Schmidt, A.,Paisdzior, S.,Szczepek, M.,Bauer, B.,Koch, A.,Gallandi, M.,Kwiatkowski, D.,Burger, J.,Mielke, T.,Beck-Sickinger, A.G.,Hildebrand, P.W.,Spahn, C.M.T.,Hilger, D.,Schacherl, M.,Biebermann, H.,Hilal, T.,Kuhnen, P.,Kobilka, B.K.,Scheerer, P.
Structures of active melanocortin-4 receptor-Gs-protein complexes with NDP-alpha-MSH and setmelanotide.
Cell Res., 31:1176-1189, 2021

PubMed 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.

PubMed: 34561620
DOI: 10.1038/s41422-021-00569-8

Experimental method

ELECTRON MICROSCOPY (2.58 Å)