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TitleStructures of active melanocortin-4 receptor-Gs-protein complexes with NDP-α-MSH and setmelanotide.
Journal, issue, pagesCell Res, Vol. 31, Issue 11, Page 1176-1189, Year 2021
Publish dateSep 24, 2021
AuthorsNicolas A Heyder / Gunnar Kleinau / David Speck / Andrea Schmidt / Sarah Paisdzior / Michal Szczepek / Brian Bauer / Anja Koch / Monique Gallandi / Dennis Kwiatkowski / Jörg Bürger / Thorsten Mielke / Annette G Beck-Sickinger / Peter W Hildebrand / Christian M T Spahn / Daniel Hilger / Magdalena Schacherl / Heike Biebermann / Tarek Hilal / Peter Kühnen / Brian K Kobilka / Patrick Scheerer /
PubMed AbstractThe 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 ...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.
External linksCell Res / PubMed:34561620 / PubMed Central
MethodsEM (single particle)
Resolution2.58 - 2.86 Å
Structure data

13453

7piu

EMDB-13453, PDB-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.
Method: EM (single particle) / Resolution: 2.58 Å

13454

7piv

EMDB-13454, PDB-7piv:
Active Melanocortin-4 receptor (MC4R)- Gs protein complex bound to agonist NDP-alpha-MSH at 2.86 A resolution.
Method: EM (single particle) / Resolution: 2.86 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-HOH:
WATER / Water

Source
  • homo sapiens (human)
  • synthetic construct (others)
  • rattus norvegicus (Norway rat)
  • bos taurus (cattle)
  • lama glama (llama)
  • mus musculus (house mouse)
KeywordsSIGNALING PROTEIN / GPCR / MELANOCORTIN-4 RECEPTOR / MELANOCORTIN RECEPTORS / SETMELANOTIDE / NDP-ALPHA-MSH / ALPHA-MSH / ANTAGONISM / AGONISM / APPETITE REGULATION / ANTI-OBESITY TREATMENT / ALPHA-18 MSH

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