Conformational features responsible for the binding of cyclic analogues of enkephalin to opioid receptors

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Abstract
Models of .mu.- and .delta.-receptor-bound backbone conformations of enkephalin cyclic analogues containing Phe4 were determined by comparing geometrical similarity among the previously found low-energy backbone structures of [D-Cys2,Cys5]-enkephalinamide, [D-Cys2,D-Cys5]-enkephalinamide, [D-Pen2,L-Pen5]-enkephalin and [D-Pen2,D-Pen5]-enkephalin. The present .mu.-receptor-bound conformation resembles a .beta.-I bend in the peptide backbone centred on the Gly3-Phe4 region. Two slightly different models were found for the .delta.-receptor-bound conformation; both of them are more extended than the .mu.-receptor-bound conformation and include a .gamma.-turn (or a .gamma.-like turn) on the Gly3 residue. Energetically favourable rotamers of Tyr and Phe side chains were also determined for the .mu.- and .delta.-conformations. The present models of .mu.- and .delta.-conformations share geometrical similarity with the low-energy structures of Leu-enkephalin and the Tyr-D-Lys-Gly-Phe-analogue.