May 31, 2002

G protein-coupled receptor allosterism and complexing

Pharmacological Reviews
Arthur Christopoulos, Terry Kenakin


G protein-coupled receptors (GPCRs) represent the largest family of cell-surface receptors. These receptors are natural allosteric proteins because agonist-mediated signaling by GPCRs requires a conformational change in the receptor protein transmitted between two topographically distinct binding sites, one for the agonist and another for the G protein. It is now becoming increasingly recognized, however, that the agonist-bound GPCR can also form ternary complexes with other ligands or "accessory" proteins and display altered binding and/or signaling properties in relation to the binary agonist-receptor complex. Allosteric sites on GPCRs represent novel drug targets because allosteric modulators possess a number of theoretical advantages over classic orthosteric ligands, such as a ceiling level to the allosteric effect and a potential for greater GPCR subtype-selectivity. Because of the noncompetitive nature of allosteric phenomena, the detection and quantification of such effects often relies on a combination of equilibrium binding, nonequilibrium kinetic, and functional signaling assays. This review discusses the development and properties of allosteric receptor models for GPCRs and the detection and quantification of alloste...Continue Reading

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Mentioned in this Paper

Allosteric Site
G-Protein-Coupled Receptors
Hormone Receptors, Cell Surface
Complex (molecular entity)
GPBAR1 gene
OXER1 gene
GTP-Binding Proteins
Radioligand Assay
Receptor Complex

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