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Vol. 54, Issue 5, 857-863, November 1998
Division of Gastroenterology and GRASP Digestive Disease
Center, Tupper Research Institute, New England Medical Center, Tufts
University School of Medicine, Boston, Massachusetts 02111
We have reported previously that the transmembrane domains of the
cholecystokinin-B/gastrin receptor (CCK-BR) comprise a putative ligand
binding pocket. In the present study, we examined whether amino
acid substitutions within the CCK-BR pocket altered the affinities
and/or functional activities of L-365,260 (the prototypical nonpeptide CCK-BR antagonist) and two structural derivatives, YM022 (a
higher affinity antagonist) and L-740,093S (a partial agonist). Eight amino acids that project into the CCK-BR pocket were
individually replaced by alanine, using site-directed mutagenesis. Affinities for the nonpeptide molecules, as well as ligand-induced inositol phosphate production, were assessed with the wild-type and
mutant receptors. For each of the nonpeptide ligands examined, a
distinct series of mutations altered the affinity, suggesting that each
ligand possessed a characteristic pattern of interactions within the
CCK-BR pocket. Basal signaling levels and inositol phosphate formation
induced by the full agonist CCK octapeptide were comparable for the
wild-type receptor and all of the mutant CCK-BR forms. In contrast to
the peptide agonist CCK octapeptide, the functional activities of the
nonpeptide molecules were selectively altered by single point mutations
within the CCK-BR pocket, resulting in interconversion of agonists and
antagonists. These findings suggest that interactions between
nonpeptide molecules and transmembrane domain amino acids of the CCK-BR
can determine the functional activity and affinity of the ligands.
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