UNIPROT:Q00604 - FACTA Search

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Three-dimensional molecular models of the human melanocortin receptor (hMC1R) have been developed based upon the electron cryo-microscopic structure of bacteriorhodopsin and the electron density footprint of bovine rhodopsin. alpha-Melanocyte-stimulating hormone, Ac-Ser-Tyr-Ser-Met4-Glu-His-Phe7-Arg-Trp-Gly-Lys-Pro-Val-NH2 (alpha-MSH, alpha-melanotropin), and the superpotent, prolonged acting agonists, Ac-Ser-Tyr-Ser-Nle4-Glu-His-DPhe7-Arg-Trp-Gly-Lys-Pro-Val-NH2 (NDP-MSH) and Ac-Nle4-c[Asp5-His6-DPhe7-Arg8-Trp9-Lys10]-NH2 (MTII), have been modeled into the proposed binding sites with specific ligand-receptor interactions identified. The melanotropin sidechain pharmacophores, DPhe7 and Trp9, are proposed to interact with a hydrophobic network of receptor aromatic residues in transmembrane regions 4, 5, 6, and 7. In addition, a hydrophilic network involving the ligand Arg8 and polar receptor residues located in transmembrane regions 2 and 3 were identified. Biological studies on alpha-MSH, NDP-MSH, MTII, and related peptides have been correlated with the proposed hMC1R model in terms of agonism, affinity, and prolongation. Finally, limited MC1R mutagenesis studies comparing alpha-MSH and NDP-MSH are interpreted within the context of the proposed hMC1R models.
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PMID:Three-dimensional molecular models of the hMC1R melanocortin receptor: complexes with melanotropin peptide agonists. 901 63

The current study aims to ascertain the fate of the melanocyte stimulating hormone (MSH) receptor and its ligand [Nle4, D-Phe7] alpha-MSH (NDP-MSH) following binding to murine B16 melanoma cells. Cells were incubated with [125I]-NDP-MSH for up to 180 min and binding, internalization and degradation determined. Intracellular trafficking of the radiolabel was assessed using Percoll density gradient centrifugation of homogenized cells. Receptor down-regulation and receptor mRNA levels were also measured over 96 hr after exposure to 1 microM ligand. NDP-MSH accumulation increased with time in a temperature-dependent manner and was inhibited by excess peptide. The ligand was rapidly internalized and translocated to the lysosomal compartment where it was degraded. Internalization was accompanied by a loss or down-regulation of cell surface receptors, suggesting internalization of the NDP-MSH-receptor complex. No recycling of the receptors between the plasma membrane and intracellular compartments could be detected in this cell-line. Approximately 15% of the surface receptors were resistant to down-regulation, possibly indicating receptor heterogeneity. Down-regulation persisted for up to 96 hr and was accompanied by a decrease in MSH receptor mRNA levels 48 hr after treatment. However, before this time, transcript levels were the same in treated and control cells. In contrast to what was seen with NDP-MSH, cell surface receptors removed with trypsin were rapidly replaced. These results show that NDP-MSH not only induced MSH receptor internalization but also inhibited receptor turnover, resulting in a prolonged down-regulation. It is concluded that, in B16 cells, the MSH receptor undergoes ligand-dependent internalization, resulting in a prolonged down-regulation.
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PMID:Binding and internalization of the melanocyte stimulating hormone receptor ligand [Nle4, D-Phe7] alpha-MSH in B16 melanoma cells. 902 81

Examination of conformationally constrained melanotropin peptide (Ac-Nle4-c[Asp5-His-Phe7-Arg-Trp9-Ala-Lys]-NH2) on four human melanotropin receptors (hMC1R, hMC3R, hMC4R, and hMC5R) resulted in identifying the importance of ligand stereochemistry at positions 5, 7, and 9 for agonist binding affinity and receptor selectivity. A trend in ligand structure-activity relationships emerged for these peptides, with the hMC1R and hMC4R possessing similar tendencies, as did the hMC3R and hMC5R. alpha-MSH (Ac-Ser-Tyr-Ser-Met4-Glu-His-Phe7-Arg-Trp-Gly-Lys-Pro-Val-NH2), NDP-MSH (Ac-Ser-Tyr-Ser-Nle4-Glu-His-D-Phe7-Arg-Trp-Gly-Lys-Pro-Val-NH2), and MTII (Ac-Nle4-c[Asp5,D-Phe7,Lys10]-alpha-MSH(4-10)-NH2) were also examined at each of these melanocortin receptors. Interestingly, the linear NDP-MSH possessed greater binding affinity for the hMC3R and hMC5R than did the cyclic analogue MTII. The peptide Ac-Nle-c[Asp-His-Phe-Arg-D-Trp9-Ala-Lys]-NH2 demonstrated the greatest differentiation in binding affinity between the hMC1R and hMC4R (78-fold). Analogue Ac-Nle-c[Asp-His-Phe7-Arg-Trp-Ala-Lys]-NH2 resulted in micromolar binding affinity (or greater) at the hMC3R and hMC5R, demonstrating the importance of D-Phe7 for ligand binding potency at these receptors. Ac-c[Asp-His-Phe-Arg-Trp-Ala-Lys]-NH2 resulted in loss of binding affinity at the hMC5R, implicating the importance of Nle4 (or a hydrophobic residue in this position) for binding to this receptor. Ac-Nle-c[D-Asp5-His-Phe-Arg-Trp-Ala-Lys]-NH2 was unable to competitively displace [125I]NDP-MSH binding at micromolar concentrations on the hMC3R and hMC5R, suggesting the importance of chirality of Asp5 either for ligand-receptor interactions or for orientation of the side chain lactam bridge and the structural integrity of the peptide conformation. Energy calculations performed for these peptides resulted in the identification of a low-energy ligand conformer family that is common to all the ligands. The differences in ligand binding affinities observed in this study are postulated to be a result of different ligand-receptor complexed interactions and not solely to the ligand structure.
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PMID:Biological and conformational examination of stereochemical modifications using the template melanotropin peptide, Ac-Nle-c[Asp-His-Phe-Arg-Trp-Ala-Lys]-NH2, on human melanocortin receptors. 917 84

The melanocortin-1 receptor (MC1R) is a seven-transmembrane (TM) G-protein-coupled receptor whose natural ligands are the melanocortin peptides, adrenocorticotropic hormone, and alpha-, beta-, and gamma- melanocyte stimulating hormone (MSH). To test a previously constructed three-dimensional model of the molecular interaction between the long-acting, superpotent alpha-MSH analog [Nle4,D-Phe7]MSH (NDP-MSH) and the human MC1R we examined the effects of site-directed receptor mutagenesis on the binding affinity and potency of NDP-MSH. In addition, we also examined the effects of these same mutations on the binding affinity and potency of the structurally related agonists alpha-MSH, gamma-MSH, and Ac-Nle4-cyclic-[Asp5,His6,D-Phe7,Arg8,Trp9,Lys10]NH2 (MT-II). Mutagenesis of acidic receptor residues Glu94 in TM2 and Asp117 or Asp121 in TM3 significantly altered the binding affinity and potency of all four agonists suggesting that these receptor residues are important to the ligand-receptor interactions of all. A disproportionate change in agonist potency versus affinity observed with simultaneous mutation of these acidic residues (mutant constructs D117A/D121A or E94A/D117A/D121A) or introduction of a single positive charge (mutant construct D121K) also implicates these residues in receptor activation. In addition, results from the individual mutation of aromatic receptor residues Phe175, Phe196, and Phe257, and simultaneous mutation of multiple TM4, -5, and -6 tyrosine and phenylalanine residues suggests that aromatic-aromatic ligand-receptor interactions also participate in binding these melanocortins to the MC1R. These experiments appear to have identified some of the critical receptor residues involved in the ligand-receptor interactions between these melanocortins and the hMC1R.
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PMID:Molecular basis for the interaction of [Nle4,D-Phe7]melanocyte stimulating hormone with the human melanocortin-1 receptor. 928 96

Recent reports show that alpha-MSH (melanocyte-stimulating hormone) is mitogenic and melanogenic for normal human melanocytes, and that this effect is mediated through binding to the melanocortin receptor (MC1R) and activation of cAMP formation. alpha-MSH has also been shown to induce changes in cell shape in melanocytes and melanoma cells, particularly increased dendricity, suggesting a potential role for alpha-MSH in melanocyte-matrix interactions and pigment transfer through reorganization of the melanocyte actin filament cytoskeleton. In this report we show that the potent alpha-MSH analog (Nle4, D-Phe7)-alpha-MSH (NDP-MSH) induces reorganization of the actin stress fiber cytoskeleton in treated human melanocytes and that this reorganization is associated with increased adhesion to fibronectin (FN). Because most melanocyte growth factors act synergistically on melanocyte mitogenesis, we also sought to determine the effect of the melanocyte mitogen endothelin-1 (ET-1) on the melanocyte actin cytoskeleton, melanocyte adhesion, and melanocyte migration. We show that ET-1, which increases melanocyte migration on FN, has opposite effects on melanocyte adhesion to FN compared with NDP-MSH and that endothelin-1-induced actin reorganization is distinct from that observed following NDP-MSH treatment. Finally, we show that focal adhesion kinase (pp125FAK), a nonreceptor tyrosine kinase associated with focal contact formation and cell migration, is phosphorylated on tyrosine residues after treatment of melanocytes with ET-1, but not NDP-MSH. These data indicate that while alpha-MSH and ET-1 act synergistically to modulate melanocyte proliferation, they have opposite effects on melanocyte-matrix interactions.
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PMID:Alpha-melanocyte-stimulating hormone and endothelin-1 have opposing effects on melanocyte adhesion, migration, and pp125FAK phosphorylation. 941 62

We synthesised nine analogues of [Nle4,D-Phe7]alpha-MSH (melanocyte-stimulating hormone) (NDP) where (1) the N- or C-terminals were deleted or exchanged by those of beta- or gamma-MSH and (2) the core residues His6, Phe7, Arg8 and Trp9 were individually substituted by Glu6, beta-(2-naphthyl)-D-alanine (D-Nal7), Lys8 and His9, respectively. We tested these analogues in ligand binding assays with cells transiently expressing the human melanocortin MC1, MC3, MC4 and MC5 receptors. The results show that the N-terminal segment (Ser1-Tyr2-Ser3) of NDP was not important for binding to melanocortin MC1 and MC4 receptors whereas it affects binding to melanocortin MC3 and MC5 receptors. The C-terminal segment (Gly10-Lys11-Pro12-Val13) of NDP was clearly important for binding to all the four melanocortin receptor subtypes. The data indicate that the low affinity of gamma-MSH for the melanocortin MC4 receptor is due to its C-terminal (Asp10)-Arg11-Phe12). Substitution of D-Phe7 by D-Nal7 increased the affinity for the melanocortin MC4 receptor but not for the other melanocortin receptor subtypes. The other core residue substitutions lowered the affinity in a differentiated manner for each of the melanocortin receptors. These results are valuable for the molecular modelling and design of selective drugs for the melanocortin receptors.
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PMID:Selective properties of C- and N-terminals and core residues of the melanocyte-stimulating hormone on binding to the human melanocortin receptor subtypes. 967 Nov 18

The possibility of developmental effects of POMC-derived melanocortins and analogs on neurons of fetal rat brain regions exhibiting marked developmental melanocortin receptor expression, was studied in serum-free co-cultures of gestational day 18 striatal and mesencephalic cells, and compared with NEI and NGE. These two peptide fragments of the melanin concentrating hormone precursor, occurring in brain areas devoid of POMC terminals, cross-react with alpha-MSH antibodies; NEI elicits grooming similar to alpha-MSH. Neurofilament protein (NF), growth-associated protein (GAP-43) and synaptophysin of the synaptosomal fraction were determined by ELISA as markers for neuritogenesis, growth cones, and nerve terminal differentiation. Cell survival was analyzed by MTT assay, proportions of major cell types by immunocytochemistry. alpha-Melanocyte-stimulating hormone (alpha-MSH, effective concentration 250-2500 nM), the analog Nle4-, D-Phe7-alpha-MSH (NDP, 3.1-750 nM), and NEI (250 nM) increased NF in 3 day cultures by 11%, 17%, and 22%, respectively, whereas ACTH(1-24) and ACTH(1-39) (25 2500 nM) were ineffective. In 11 day cultures, alpha-MSH (250-750 nM), but not NDP, ACTH(1-24) or ACTH(1-39), increased synaptosomal synaptophysin by 11%. GAP-43 and cell survival remained unaffected. These data indicate that selected melanocortins as well as NEI can influence differentiation of neural processes in brain neurons.
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PMID:Melanocortin and MCH precursor-derived NEI effects on striatum-midbrain co-cultures. 980 45

Lateral cerebroventricular (LCVT) administration of the alpha-MSH agonist analog Nle4DPhe7alpha-MSH (NDP-MSH) inhibited food intake in food-deprived rats, but did not inhibit water intake in water-deprived rats. When NDP-MSH was administered into the fourth ventricle (4CVT), comparable suppressions of food intake were observed. LCVT and 4CVT administration of NDP-MSH also reduced spontaneous 24 h food intake. LCVT injection of NDP-MSH greatly attenuated food intake stimulated in sated rats by acute CVT administration of neuropeptide Y (NPY). These and other data suggest that alpha-MSH is an important endogenous regulator of food intake, possibly acting downstream of NPY. In an attempt to assess further the sites of action of NDP-MSH, a qualitative mapping study of Fos-like immunoreactive (Fos-ir) neurons was performed following LCVT administration of NDP-MSH. LCVT injection of NDP-MSH induced Fos-ir in several forebrain regions including cortex, striatum, bed nucleus of the stria terminalis, paraventricular nucleus of the hypothalamus and arcuate nucleus. The combination of NPY and NDP-MSH did not produce obvious antagonism or cancellation of effects in any region examined. Thus, the site(s) of action of NDP-MSH on food intake remain to be clarified.
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PMID:Central injection in rats of alpha-melanocyte-stimulating hormone analog: effects on food intake and brain Fos. 987 51

The genes encoding the melanocortin-3 receptor and melanocortin-5 receptor have been cloned from rhesus monkey. Heterologous expression in CHO cells indicated species dependent in vitro pharmacological properties for the human and rhesus melanocortin-5 receptors. Several peptides including NDP-alpha-MSH, alpha-MSH, MT-II and ACTH1-24 are more potent at the rhesus melanocortin-5 receptor than the human melanocortin-5 receptor by more than 10-fold. In contrast, we found no species difference in pharmacological properties between the human and rhesus melanocortin-3 receptors. Such a species-dependent pharmacological difference for melanocortin-5 receptor appears to be an exception compared to other G protein-coupled receptors from human and rhesus monkey.
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PMID:Species-dependent pharmacological properties of the melanocortin-5 receptor. 1071 96

Reduction of disulfide bonds in human melanocortin 1 receptor (hMC1R) with increasing concentrations of DTT (dithiothreitol) resulted in a decrease in the binding of [125I]-ACTH (adrenocorticotropic hormone, L-isomer) in an uniphasic manner and a decrease in [125I]-NDP-MSH ([Nle(4),D-Phe(7)]-alpha-melanocyte stimulating hormone; D-isomer) binding in a biphasic manner. Pretreatment of hMC1R with 10 mM DTT resulted in a 36-fold loss of affinity for alpha-MSH (L-isomer) without affecting the affinity of NDP-MSH (D-isomer). To characterize the role of individual cysteine residues, we employed site-directed mutagenesis to substitute cysteine by glycine at all fourteen positions in hMC1R and analysed wild-type and mutant receptors for ligand binding and cAMP signalling. Single point mutation of four cysteine residues in extracellular loops to glycine (C35G, C267G, C273G, and C275G) resulted in a complete loss of binding for [125I]-NDP-MSH. Moreover, mutants with normal ligand binding, at positions C191G (transmembrane segment 5), C215G (third intracellular loop), and C315G (C-terminal loop) failed to generate cAMP signal in response to both agonists alpha-MSH and NDP-MSH. Mutant at position C78G (with wild-type binding to alpha-MSH as well as NDP-MSH) generated a cAMP signal in response to alpha-MSH (identical to wild-type hMC1R) but interestingly could not be stimulated by NDP-MSH. Moreover, this single amino acid substitution converted NDP-MSH from being an agonist to antagonist at the C78G mutant receptor. These findings demonstrate that (i) alpha-MSH and ACTH (L-isomers) are different from D-isomer NDP-MSH in their sensitivity to DTT for receptor binding, (ii) cysteine residues in N-terminus and extracellular loop three make disulfide bridges and are needed for structural integrity of hMC1R, (iii) cysteine residues in transmembrane segments and intracellular loops are required for receptor-G-protein coupling, (iv) C78 in transmembrane segment two is required for generating a functional response by D-isomer agonist (NDP-MSH) but not by L-isomer agonist (alpha-MSH), and (v) wild-type receptor agonist NDP-MSH is an antagonist at the mutant C78G receptor.
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PMID:Cysteine residues are involved in structure and function of melanocortin 1 receptor: Substitution of a cysteine residue in transmembrane segment two converts an agonist to antagonist. 1123 37

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