Despite similar tripeptide N-termini, dermorphin (Tyr-D-Alla-Phe-Gly-Tyr-Pro-Ser-NH2) and dermenkephalin (Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2), naturally occuring opioid peptides from frog skin, exhibit high affinity but contrasting selectivity for the mu- and delta-opioid receptors, respectively. Structure-activity relationship studies have shown that the N-terminal tripeptide, Tyr-D-Xaa-Phe (where Xaa is either Ala or Met), is necessary for binding with both the mu- and delta-receptors while the nature and/or the conformation of the C-terminus His-Leu-Met-Asp-NH2 of dermenkephalin are responsible for addressing the peptide to the delta-receptor. In order to examine the conformational characteristics that are related to the selectivity of dermenkephalin towards the delta-receptor, 50 NOE restraints (10 between non-adjacent residues), and 7 dihedral angles, derived from a two-dimensional H-1-NMR study of dermenkephalin in dimethyl sulfoxide, were used in simulated annealing and energy minimization procedures. Twenty-four resulting conformers (60% of the generated structures) with no severe distance restraint violation were pooled into seven groups and three related families. These 24 conformers show close proximity between the two methionine residues, S-shaped structures, mean planes of N-terminal and C-terminal moieties almost at right angles to each other, a C-terminus region above the plane of the N-terminal region and g(-) as preferential orientation in the side chain of Phe. Aside these similarities, families of conformers differ by the preferential orientation in the side chain of Tyr (t or g(-)) and proximity between Tyr and Asp, or Tyr and the C-terminus. In contrast to previous models, practically no beta-turn structures exist for dermenkephalin, most of the NH hydrogen bonds participating to gamma-turns. The possible relationship between the conformational characteristics of dermenkephalin and the delta-opioid receptor selectivity is discussed. (C) Munksgaard 1996.
