SOLUTION STRUCTURES OF THE MELANOCYTE-STIMULATING HORMONES BY 2-DIMENSIONAL NMR-SPECTROSCOPY AND DYNAMICAL SIMULATED ANNEALING CALCULATIONS

Melanocortins, which are involved in melanocyte pigmentation control a nd glucocorticoid stimulation, have functional roles in various physio logical mechanisms and have been shown to participate in higher cortic al functions. Recently, it has also been reported that melanocyte stim ulating hormone (MSH) and melanocortin 4 receptor (MC4R) are the key c omponents of the hypothalamic response to obesity. The solution struct ures of both melanocyte-stimulating hormone alpha-MSH r-Ser-Met-Glu-Hi s-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2) and its analog alpha-MSH-ND (Ac-Ahx -Asp-His-DPhe-Arg-Trp-Lys-NH2) (Ahx, 2-aminohexanoic acid) have been d etermined by two-dimensional NMR spectroscopy and simulated-annealing calculations. The NMR data revealed that alpha-MSH forms a hairpin loo p conformation which includes conserved message sequences, whereas alp ha-MSH-ND prefers a type I beta-turn comprising residues of Asp2-His3- DPhe4-Arg5. Final simulated-annealing structures of both alpha-MSH-ND and alpha-MSH peptides converged with rmsd of 0.07 nm for alpha-MSH-ND and 0.1 nm for alpha-MSH between backbone atoms, respectively. This r esult will provide the structural bases of melanocortin functions as w ell as valuable information for structure-based drug design involving the regulation of obesity and feeding.