Mutational analysis of the putative devazepide binding site of the CCK-A receptor
| Autor: | O. J. A. E. Ophorst, Peter H.G.M. Willems, S.E. van Emst-de Vries, H.P.H. Hermsen, Adriaan P. IJzerman, R.L.L. Smeets, J.J.H.H.M. De Pont |
|---|---|
| Rok vydání: | 1997 |
| Předmět: |
DNA
Complementary Molecular model Stereochemistry medicine.drug_class DNA Mutational Analysis Mutant Devazepide Carboxamide CHO Cells Biology Transfection Sincalide Substrate Specificity Iodine Radioisotopes Hormone Antagonists Cricetinae medicine Animals Binding site Receptor GeneralLiterature_REFERENCE(e.g. dictionaries encyclopedias glossaries) Pharmacology chemistry.chemical_classification Benzodiazepinones Binding Sites Antagonist Hydrogen Bonding Desensitizering van de CCK-A receptor Receptor Cholecystokinin A Amino acid Kinetics Desensitization of the CCK-A receptor chemistry Biochemistry Mutagenesis Calcium Receptors Cholecystokinin |
| Zdroj: | European Journal of Pharmacology, 325, pp. 93-99 European Journal of Pharmacology, 325, 93-99 European Journal of Pharmacology, 325, 1, pp. 93-99 |
| ISSN: | 0014-2999 |
| DOI: | 10.1016/S0014-2999(97)00106-4 |
| Popis: | Recently a molecular model was proposed for the binding site of the antagonist 3 S (−)- N -(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1 H -1,4-benzodiazepine-3-yl)-1 H -indole-2-carboxamide (devazepide) on the cholecystokinin-A (CCK A ) receptor ( Van der Bent et al., 1994 . Drug Design Discov. 12, 129–148). Fifteen amino acids were identified, including hydrophilic ones such as Ser 139 , Asn 349 and Ser 379 , that might interact with the carboxamide moiety in devazepide. To provide mutational evidence for this model, wild-type and mutant receptors (S139A, N349A and S379A) were transiently expressed and compared with respect to the ability of devazepide to inhibit binding of radiolabelled cholecystokinin-(26–33)-peptide amide (CCK-8) and CCK-8-evoked Ca 2+ mobilization. The data presented suggest the involvement of the three residues in antagonist binding, although to a different extent. However, it does not seem likely that hydrogen bonds are the driving force in view of the relatively minor changes in receptor affinity and activity. © 1997 Elsevier Science B.V. |
| Databáze: | OpenAIRE |
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