Interactions of the melanocortin-4 receptor with the peptide agonist NDP-MSH.
Bottom Line: For the first time, the interactions between the terminal regions of NDP-MSH and the receptor are described.The amino-terminus appears to be adjacent to a series of hydrophilic residues with novel interactions at Cys196 (TM5) and Asp189 (extracellular loop 2).These interactions are reminiscent of sequential ligand binding exhibited by the beta(2)-adrenergic receptor, with the former interaction being equivalent to the known interaction involving Ser204 of the beta(2)-adrenergic receptor.
Affiliation: School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, UK.Show MeSH
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Mentions: Experiments were performed to cross-link the NDP-MSH Cys analogues to the WT receptor. Figure 4 illustrates the cross-linking of peptide analogues to the native receptor when Cys is present near the amino-terminus of the peptide (particularly at position 2) or near the carboxyl-terminus of the peptide (positions 12 and 13). These data suggested that one or more Cys residues in the WT receptor (there are 15 Cys residues in MC4R) make a direct contact with residues close to the amino-terminus and carboxyl-terminus of the agonist NDP-MSH. The Kd values for cysteine substitutions at positions 1, 2, 10, and 11 were not significantly different from the native peptide (Student's t test, p > 0.05; data not shown). In contrast, binding affinity was not readily detectable with cysteine substitutions at positions His-Phe-Arg-Trp (unpublished data).
Affiliation: School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, UK.