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Updated: Oct 22, 2025

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Structural insights into ligand recognition and activation of the melanocortin-4 receptor

Huibing Zhang1,2,3,4, Li-Nan Chen1,2,3,4, Dehua Yang5,6,7

  • 1Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

Cell Research
|August 26, 2021
PubMed

Insights

Researchers uncovered the structure of the Melanocortin-4 receptor (MC4R) bound to various molecules. This provides crucial insights into how MC4R is activated, potentially aiding the development of new obesity treatments.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Pharmacology

Background:

  • The Melanocortin-4 receptor (MC4R) is vital for regulating energy balance.
  • Challenges in MC4R drug development stem from its similarity to other receptors and lack of structural data.

Purpose of the Study:

  • To determine the high-resolution structures of MC4R in complex with Gs protein.
  • To elucidate the molecular mechanisms of MC4R activation by different ligands.

Main Methods:

  • X-ray crystallography to obtain high-resolution structures.
  • Pharmacological studies to assess ligand binding and receptor activation.

Main Results:

  • Structures of MC4R complexed with Gs protein, α-MSH, afamelanotide, bremelanotide, and THIQ were determined.
  • Conserved binding modes for peptide agonists and distinct recognition for small molecules were revealed.
  • A unique MC4R activation mechanism and G protein coupling insights were uncovered.

Conclusions:

  • Structural and pharmacological data illuminate MC4R activation and selectivity.
  • Findings pave the way for designing selective MC4R therapeutics for obesity and related metabolic disorders.

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