Benzodiazepine ligands can act as allosteric modulators of the Type 1 cholecystokinin receptor

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Abstract

The cholecystokinin (CCK1) receptor is a G protein-coupled receptor important for nutrient homeostasis. The molecular basis of CCK-receptor binding has been debated, with one prominent model suggesting occupation of the same region of the intramembranous helical bundle as benzodiazepines. Here, we used a specific assay of allosteric ligand interaction to probe the mode of binding of devazepide, a prototypic benzodiazepine ligand. Devazepide elicited marked slowing of dissociation of pre-bound CCK, only possible through binding to a topographically distinct allosteric site. This effect was disrupted by chemical modification of a cysteine in the benzodiazepine-binding pocket. Application of an allosteric model to the equilibrium interaction between a series of benzodiazepine ligands and CCK yielded quantitative estimates of each modulator’s affinity for the allosteric site, as well as the degree of negative cooperativity for the interaction between occupied orthosteric and allosteric sites. The allosteric nature of benzodiazepine binding to the CCK1 receptor provides new opportunities for small molecule drug development.

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Supported by grants from the National Institutes of Health Grant DK32878 (L.J.M.), the National Health and Medical Research Council of Australia (NHMRC) Grant 400134 (A.C., P.M.S.) and by the Fiterman Foundation. P.M.S. is a NHMRC Principal Research Fellow. A.C. is a NHMRC Senior Research Fellow.

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