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Study · Not a test of the peptide alone · 2021

2 results

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

Heyder NA, Kleinau G, Speck D, Schmidt A, Zschunke S, Szczepek M, Bauer B, Koch A, Gallandi M, Kwiatkowski D, Bürger J, Mielke T and 10 more

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Beck-Sickinger AG, Hildebrand PW, Spahn CMT, Hilger D, Schacherl M, Biebermann H, Hilal T, Kühnen P, Kobilka BK, Scheerer P

Cell research24 Sept 2021Cited by 85 (Europe PMC)

PMID34561620 (opens in a new tab)PMCIDPMC8563958 (opens in a new tab)DOI10.1038/s41422-021-00569-8 (opens in a new tab)PepBankPUB-34561620
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Summary

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.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study2

No result from this study comes from a test of the peptide.

Studies that did not test the peptide alone2

In this study, Setmelanotide was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Setmelanotide.

  1. 01LabNot a test of Setmelanotide aloneIn vitro (cell-free)Mechanism

    In lab tests, the setmelanotide-bound MC4R-Gs-protein complex structure had 2.6 Å resolution.

    In plain wordsIn lab tests, the setmelanotide-bound receptor complex structure had 2.6 Å resolution.

    Peptide
    Setmelanotide
    Outcome
    Not applicableSetmelanotide-bound structure resolution
    Study

    n: not reported in source

    MC4R-Gs-protein complex
    Outcome group
    Receptor activity and mechanism · Pharmacology

    Source sentences

    Summary
    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.

    In this study, Setmelanotide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Setmelanotide.

  2. 02LabNot a test of Setmelanotide aloneIn vitro (cell-free)Mechanism

    In lab tests, setmelanotide binding implicated TM3 in ligand-specific interactions and calcium as a ligand-adaptable cofactor.

    In plain wordsIn lab tests, setmelanotide binding implicated TM3 in specific binding interactions and calcium as a cofactor.

    Peptide
    Setmelanotide
    Outcome
    Not applicableLigand-specific binding interactions
    Study

    n: not reported in source

    MC4R-Gs-protein complex
    Outcome group
    Receptor activity and mechanism · Pharmacology

    Source sentences

    Summary
    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.

    In this study, Setmelanotide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Setmelanotide.

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

  1. Version 3Current

    28 Oct 2026, 02:03 UTC

    Study results updated

  2. Version 2

    27 Oct 2026, 16:36 UTC

    Study data updated · source update from Europe PMC

  3. Version 1

    13 Oct 2026, 16:31 UTC

    First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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