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
Related in: MedlinePlus
Mentions: In the model, the C-terminus of the peptide ligand is close to the extracellular end of TM6 and TM7, and ECL3 (Fig. 7). Western blot analysis of peptide 13 demonstrates cross-linking of the peptide to all of the mutant receptors, except for C257A-MC4R, implying that the carboxyl-terminus interacts with TM6 (Fig. 3). The Cys(6.47) residue is located on TM6 of the MC4R (Cys257) just below the hydrophobic pocket (Trp257, Phe261, Tyr268, and Ile269). It is conceivable that due to TM6 flexibility, Cys257 in the MC4R may be more accessible in the active state of the receptor.
Affiliation: School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, UK.