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

Fan Gao, Patrick M. Sexton, Arthur Christopoulos, Laurence J. Miller

Research output: Contribution to journalArticle

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4401-4404
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume18
Issue number15
DOIs
StatePublished - Aug 1 2008

Keywords

  • Allosteric modulators
  • Cholecystokinin receptor
  • Cooperativity
  • G protein-coupled receptors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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