Avlani_2007_J.Biol.Chem_282_25677

Reference

Title : Critical role for the second extracellular loop in the binding of both orthosteric and allosteric G protein-coupled receptor ligands - Avlani_2007_J.Biol.Chem_282_25677
Author(s) : Avlani VA , Gregory KJ , Morton CJ , Parker MW , Sexton PM , Christopoulos A
Ref : Journal of Biological Chemistry , 282 :25677 , 2007
Abstract :

The second extracellular (E2) loop of G protein-coupled receptors (GPCRs) plays an essential but poorly understood role in the binding of non-peptidic small molecules. We have utilized both orthosteric ligands and allosteric modulators of the M2 muscarinic acetylcholine receptor, a prototypical Family A GPCR, to probe possible E2 loop binding dynamics. We developed a homology model based on the crystal structure of bovine rhodopsin and predicted novel cysteine substitutions that should dramatically reduce E2 loop flexibility via disulfide bond formation and significantly inhibit the binding of both types of ligands. This prediction was validated experimentally using radioligand binding, dissociation kinetics, and cell-based functional assays. The results argue for a flexible "gatekeeper" role of the E2 loop in the binding of both allosteric and orthosteric GPCR ligands.

PubMedSearch : Avlani_2007_J.Biol.Chem_282_25677
PubMedID: 17591774

Related information

Citations formats

Avlani VA, Gregory KJ, Morton CJ, Parker MW, Sexton PM, Christopoulos A (2007)
Critical role for the second extracellular loop in the binding of both orthosteric and allosteric G protein-coupled receptor ligands
Journal of Biological Chemistry 282 :25677

Avlani VA, Gregory KJ, Morton CJ, Parker MW, Sexton PM, Christopoulos A (2007)
Journal of Biological Chemistry 282 :25677