Molecular basis for binding and subtype selectivity of 1,4-benzodiazepine antagonist ligands of the cholecystokinin receptor

Show simple item record Cawston, Erin en Sexton, PM en Miller, LJ en
dc.coverage.spatial Ventura, CA, USA en 2012-04-12T00:40:53Z en 2011-01 en
dc.identifier.citation Gordon Research Conference, Molecular Pharmacology. 2011 en
dc.identifier.uri en
dc.description.abstract Allosteric intramembranous binding pockets in peptide-binding GPCRs create opportunities to develop novel small molecule drugs with substantial benefit over orthosteric-acting drugs. To gain insights into the molecular determinants of the allosteric binding pocket within cholecystokinin (CCK) receptors, we prepared and characterized a series of receptor constructs in which residues proposed to line this pocket that are distinct in each receptor were reversed (chimeric constructs). Two novel ligands were studied, representing 1,4-benzodiazepine antagonists that differ only in the stereochemistry (S or R) of the 3-position side chain, while exhibiting binding selectivity for either CCK1R or CCK2R, respectively. Radioiodinated 1,4-benzodiazepine ligands were used as tracers in the binding assays. Six mutations within four transmembrane segments of CCK1R and CCK2R were studied. When all six residues were mutated in CCK1R to the corresponding residues in CCK2R, the selectivity of this receptor was completely reversed, yet its peptide-binding selectivity was unaffected. To further investigate which regions may be responsible for this change in selectivity, mutagenesis of the residues within individual transmembrane segments within CCK1R and CCK2R was performed and resulted in minimal impact in binding to the iodinated 1,4-benzodiazepines. Therefore, combining the residue changes within two or three segments were also prepared and studied. This detailed mutational analysis provides important information on the benzodiazepine allosteric binding site present within the CCK receptors and provides insight into ligand-receptor interactions that may be important in selectivity of this allosteric binding pocket within CCK receptors. en
dc.relation.ispartof Gordon Research Conference, Molecular Pharmacology en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri en
dc.title Molecular basis for binding and subtype selectivity of 1,4-benzodiazepine antagonist ligands of the cholecystokinin receptor en
dc.type Conference Poster en en
dc.rights.accessrights en
pubs.elements-id 323433 en Medical and Health Sciences en Medical Sciences en Pharmacology en
pubs.record-created-at-source-date 2012-03-15 en

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