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J Biol Chem, Vol. 274, Issue 33, 23191-23197, August 13, 1999

Evidence for a Direct Interaction between the Penultimate Aspartic Acid of Cholecystokinin and Histidine 207, Located in the Second Extracellular Loop of the Cholecystokinin B Receptor

Sandrine Silvente-Poirot, Chantal Escrieut, Céline Galès, Jean-Alain Fehrentz^¶, Achim Escherich, Stephen A. Wank^**, Jean Martinez^¶, Luis Moroder, Bernard Maigret, Michelle Bouisson, Nicole Vaysse, and Daniel Fourmy

From  INSERM U 151, Institute Louis Bugnart, CHU Rangueil, Bat L3, 31403 Toulouse Cedex, France, ^¶ CNRS, UMR 5810, Faculté de Pharmacie, 34060 Montpellier, France,  Laboratoire de Chimie Théorique, Université de Nancy, 54506 Vandoeuvre, Nancy, France, ^** Digestive Diseases Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892-1804, and  Max Planck Institute für Biochemie, 82143 Martinsried, Federal Republic of Germany

Recently, we reported that the mutation of His²⁰⁷ to Phe located in the second extracellular loop of the cholecystokinin B receptor strongly affected cholecystokinin (CCK) binding (Silvente-Poirot, S., Escrieut, C., and Wank, S. A. (1998) Mol. Pharmacol. 54, 364-371). To characterize the functional group in CCK that interacts with His²⁰⁷, we first substituted His²⁰⁷ to Ala. This mutation decreased the affinity and the potency of CCK to produce total inositol phosphates 302-fold and 456-fold without affecting the expression of the mutant receptor. The screening of L-alanine-modified CCK peptides to bind and activate the wild type and mutant receptors allowed the identification of the interaction of the C-terminal Asp⁸ of CCK with His²⁰⁷. The H207A-CCKBR mutant, unlike the wild type receptor, was insensitive to substitution of Asp⁸ of CCK to other amino acid residues. This interaction was further confirmed by mutating His²⁰⁷ to Asp. The affinity of CCK for the H207D-CCKBR mutant was 100-fold lower than for the H207A-CCKBR mutant, consistent with an electrostatic repulsion between the negative charges of the two interacting aspartic acids. Peptides with neutral amino acids in position eight of CCK reversed this effect and displayed a gain of affinity for the H207D mutant compared with CCK. To date, this is the first report concerning the identification of a direct contact point between the CCKB receptor and CCK.

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