Comparison of the structure‐activity relationships of nociceptin and dynorphin A using chimeric peptides

FEBS Letters

Moisand, Christiane¹  Mollereau, Catherine¹  Mazarguil, Honoré¹  Meunier, Jean-Claude¹  Lapalu, Sophie¹  Cambois, Gilles¹ 

[1] Unité de Neuropharmacologie Moléculaire, Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique, 205 route de Narbonne, 31077 Toulouse cedex 4, France

关键词: Structure-activity relationship;    Dynorphin A;    Nociceptin/orphanin FQ;    Chimeric neuropeptide;    Opioid and opioid receptor-like receptor;    ORL1;    opioid receptor-like 1;    noc;    nociceptin;    dyn;    dynorphin A;    nd;    nociceptin/dynorphin A hybrid peptide;    dn;    dynorphin A/nociceptin hybrid peptide;   

DOI  :  10.1016/S0014-5793(97)01318-5

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

The aim of the present study was to delineate the functional domains of nociceptin (noc), a neuropeptide which is structurally related to dynorphin A (dyn). The binding and biological potencies towards the nociceptin (ORL1) and dynorphin A (κ-opioid) receptors of twenty dyn/noc and noc/dyn hybrid peptides were compared with those of the parent heptadecapeptides. Replacement of as many as eleven residues in the C-terminus of dynorphin by the corresponding nociceptin sequence has no significant effect on binding and biological activity towards the κ-opioid receptor. In marked contrast, replacement of as few as six residues (RKLANQ) in the C-terminus of nociceptin by the corresponding dynorphin sequence (LKWDNQ) dramatically impairs both affinity and activity towards the ORL1 receptor. This clearly indicates that the two neuropeptides have different functional architectures, despite the dual structural homology of both ligands and receptors. Moreover, the recombinant peptide approach led us to identify hybrids whose sequences differ only at positions 5 and 6 and displaying opposite or no receptor selectivity. One contains the dynorphin Leu⁵-Arg⁶ sequence and prefers the κ-opioid receptor, whereas the other comprises the nociceptin Thr⁵-Gly⁶ sequence and prefers the ORL1 receptor. A third, containing the mixed dynorphin/nociceptin Leu⁵-Gly⁶ sequence, does not discriminate between the two types of receptor.

【 授权许可】

Unknown