Dermenkephalin and deltorphin I reveal similarities within ligand-binding domains of μ- and δ-opioid receptors and an additional address subsite on the δ-receptor

Abstract : Dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2), dermenkephalin (Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2) and deltorphin I (Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2) are the first naturally occurring peptides highly potent for and almost specific to the mu- and delta-opioid receptors, respectively. The amino-terminal domains Tyr-D-X-Phe (where X is either Ala or Met) of these peptides behave as selective and potent mu-receptor ligands. Routing of Tyr-D-X-Phe to the delta- or the mu- receptor is associated with the presence or the absence at the C-terminus of an additional hydrophobic and negatively charged tetrapeptide by-passing the mu-addressing ability of the amino-terminal moiety. A study of 20 Tyr-D-X-Phe-Y-NH2 analogs with substitution of X and Y by neutral, hydrophobic, aromatic amino acids as well as by charged amino acid residues shows that tetrapeptides maintain high binding affinity and selectivity for the mu-opioid receptor. Although residue in position 4 serves a delta-address function, the tripeptide motif at the C-terminus of dermenkephalin and deltorphin I are critical components for high selectivity at delta-opioid receptor. Results demonstrate that mu- and delta-opioid receptors share topologically equivalent ligand-binding domains, or ligand-binding sequences similarities, that recognized Tyr-D-X-Phe as a consensus message-binding sequence. The delta-receptor additionally contains a unique address subsite at or near the conserved binding domain that accommodates the C-terminal tetrapeptide motif of dermenkephalin and deltorphin I.
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Submitted on : Wednesday, July 3, 2019 - 11:35:01 AM
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Stéphane Charpentier, Sandrine Sagan, Antoine Delfour, Pierre Nicolas. Dermenkephalin and deltorphin I reveal similarities within ligand-binding domains of μ- and δ-opioid receptors and an additional address subsite on the δ-receptor. Biochemical and Biophysical Research Communications, Elsevier, 1991, 179 (3), pp.1161-1168. ⟨10.1016/0006-291x(91)91693-7⟩. ⟨hal-02171883⟩

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