Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding

Some calcium is required for binding The melanocortin-4 receptor (MC4R) coordinates food intake and energy expenditure and is a target for treating obesity. MC4R is an unusual G protein–coupled receptor, in part because it binds either an endogenous agonist or an endogenous antagonist, leading to reduced appetite or increased food intake, respectively. Yu et al. determined the structure of MC4R bound to an antagonist (see the Perspective by Chaturvedi and Shukla). This structure revealed a calcium ion coordinated by the receptor and the antagonist. Biochemical studies showed that the calcium ion also increased the affinity for endogenous agonist, which translated into increased potency. The authors also confirm a previous finding that MC4R directly couples to the ion channel Kir7.1 and regulates channel gating. Science, this issue p. 428; see also p. 369 The G protein–coupled receptor melanocortin-4 binds Ca2+ and ligand at the same site and directly couples to Kir7.1 ion channels. 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. Ca2+ is identified as a cofactor that is complexed with residues from both the receptor and peptide ligand. Extracellular Ca2+ 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.

• Publication year

  2020

• Venue

  Science

• Publication date

  2020-04-24

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1126/science.aaz8995PMID 32327598PMCID PMC7567314
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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