AI Article Synopsis
- The melanocortin-4 receptor (MC4R) plays a key role in regulating energy balance and is a significant target for obesity treatments.
- Researchers determined the structure of the human MC4R when bound to the antagonist SHU9119, revealing a cofactor (calcium) that enhances receptor interactions.
- The study demonstrates that MC4R operates through a unique signaling mechanism, different from traditional G protein-coupled receptors, and shows greater structural similarity to lipidic than peptidic GPCRs.
Article Abstract
The melanocortin-4 receptor (MC4R) is involved in energy homeostasis and is an important drug target for syndromic obesity. We report the structure of the antagonist SHU9119-bound human MC4R at 2.8-angstrom resolution. Ca is identified as a cofactor that is complexed with residues from both the receptor and peptide ligand. Extracellular Ca increases the affinity and potency of the endogenous agonist α-melanocyte-stimulating hormone at the MC4R by 37- and 600-fold, respectively. The ability of the MC4R crystallized construct to couple to ion channel Kir7.1, while lacking cyclic adenosine monophosphate stimulation, highlights a heterotrimeric GTP-binding protein (G protein)-independent mechanism for this signaling modality. MC4R is revealed as a structurally divergent G protein-coupled receptor (GPCR), with more similarity to lipidic GPCRs than to the homologous peptidic GPCRs.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567314 | PMC |
| http://dx.doi.org/10.1126/science.aaz8995 | DOI Listing |
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