Solution conformations of deltorphin-I obtained from combined use of quantitative 2D-NMR and energy calculations: A comparison with dermenkephalin

Deltorphin-1, Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2 and dermenkephalin, Tyr-D-M et-Phe-His-Leu-Met-Asp-NH2, two highly related opioid peptides from frog sk in, display very similar N-termini but strikingly different C-terminal tail s. Nevertheless, both peptides are highly potent at, and exquisitely select ive for the delta-opioid receptor. To identify common determinants concurin g to the remarkably efficient targeting of deltorphin-1 and dermenkephalin, combined use of quantitative two-dimensional nuclear magnetic resonance (5 3 dipolar interactions studied at four temperatures) and energy calculation s using simulated annealing generated five groups of deltorphin-1 conformer s. These groups were pooled into two families whose overall conformation co uld be described either by a left-handed helix (Family I) or by a big loop (Family II), both stabilized by H-bonds. Proximity of D-Ala(2)-Phe(3)-Asp(4 ) and Val(5)-Val(6)-Gly(7) triads is an obvious structural similarity betwe en almost all groups in both families of structures. Whereas differences be tween the two families originated mostly from a transition at psi Asp(4) ba ckbone dihedral angle, the backbone structures at segment 1-4 are similar a nd spatial arrangements of Tyr(1) (t) and Phe(3) (g(-)) are identical in on e group of each family. Moreover, these two groups have a N-terminal tetrap eptide whose conformation most closely resembles that of a well-defined gro up of structures for dermenkephalin. Altogether, these results suggest that conformational attributes that are common to dermenkephalin and deltorphin -1, i.e., the backbone conformation of the N-terminal tetrapeptide and pref erential orientations in the side-chain of Tyr(1) (t) and Phe3 (g(-)) under lie their ability to bind with high selectivity to the delta-opioid recepto r.