Abstract
Agouti and agouti-related protein (AgRP) are endogenous antagonists of the melanocortin receptors (MCxR). Previous data showed that recombinant full-length agouti and a synthetic fragment of AgRP, AgRP (83-132), are inverse agonists at the MC1R and MC4R, respectively. This study demonstrates the smaller analogs AgRP (87-120) and ASIP [90-132 (L89Y)], and short peptides Yc[CRFFNAFC]Y and Qc[CRFFRSAC]S are also MC4R inverse agonists. Furthermore, the relative affinity of the series of MC4R ligands for displacement of radiolabeled antagonist 125I-AgRP (86-132) versus radiolabeled agonist 125I-NDP-MSH did not correlate with ligand efficacy, which is more consistent with an induced-fit model than a simple two-state model of MC4R activation. These data shed new light on the determinants and mechanism of inverse agonism at the MC4R.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Agouti Signaling Protein
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Agouti-Related Protein
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Amino Acid Motifs
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Cell Line
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Cyclic AMP / metabolism
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Dose-Response Relationship, Drug
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Humans
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Hypothalamus / pathology
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Intercellular Signaling Peptides and Proteins / physiology*
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Kinetics
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Ligands
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Melanocyte-Stimulating Hormones / pharmacology
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Models, Molecular
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Obesity
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Peptides / chemistry
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Peptides, Cyclic / pharmacology
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Pigmentation
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Protein Binding
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Protein Structure, Tertiary
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Proteins / physiology*
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Receptors, Melanocortin / antagonists & inhibitors
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Receptors, Melanocortin / chemistry
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Recombinant Proteins / chemistry
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alpha-MSH / metabolism
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beta-MSH / analogs & derivatives*
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beta-MSH / pharmacology
Substances
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11-Mrp-14-Nal-18-Cys-22-Asp-beta-MSH(11-22)NH2
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AGRP protein, human
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Agouti Signaling Protein
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Agouti-Related Protein
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Intercellular Signaling Peptides and Proteins
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Ligands
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Peptides
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Peptides, Cyclic
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Proteins
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Receptors, Melanocortin
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Recombinant Proteins
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beta-MSH
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SHU 9119
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alpha-MSH
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Melanocyte-Stimulating Hormones
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Cyclic AMP