Identification of two amino acids of the human cholecystokinin-A receptor that interact with the N-terminal moiety of cholecystokinin.

The Journal of Biological Chemistry
K KennedyD Fourmy

Abstract

A region between residues 38 and 42 of the human cholecystokinin-A (CCK-A) receptor was shown to be involved in the binding of CCK but not in that of JMV 179 and JMV 180, two peptides closely related to CCK (Kennedy, K., Escrieut, C., Dufresne, M., Clerc, P., Vaysse, N., and Fourmy, D. (1995) Biochem. Biophys. Res. Commun. 213, 845-852). In the present study, we have identified the residues of both the receptor and the ligand responsible for this differential binding. Residues Trp-39 and Gln-40 of the receptor were crucial for binding of the C-terminal nonapeptide of CCK as W39F and Q40N mutants demonstrated parallel decreases in both affinity and potency to induce accumulation of inositol phosphates (12.9- and 20.9-fold). The W39F and Q40N mutant receptors bound CCK analogues modified at their C-terminal end, including JMV 179 and JMV 180, as well as the C-terminal amidated heptapeptide of CCK, with identical affinities to the wild-type receptor. In contrast, W39F and Q40N mutants bound CCK octapeptide with the same decreased affinity as the CCK nonapeptide. The modeling of the CCK-A receptor and the docking of the peptide agonists [Thr,Nle]CCK9 and CCK-8 indicated that their N terminus was connected to the receptor through a ...Continue Reading

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Aug 10, 2001·Journal of Peptide Science : an Official Publication of the European Peptide Society·S De LucaG Morelli
Aug 1, 2002·Journal of Peptide Science : an Official Publication of the European Peptide Society·Giancarlo MorelliUlderico Mazzi
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Jun 19, 2008·Pharmacology & Therapeutics·Laurence J Miller, Fan Gao
Apr 5, 2003·Journal of Peptide Science : an Official Publication of the European Peptide Society·Stefania De LucaGiancarlo Morelli
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