Abstract
Background:
Many researchers have tried to correlate characteristics of ligand binding at G-protein-coupled receptor (GPCR) with ligand efficacy. The ternary complex model (TCM) is the traditional model for explaining the equilibrium of agonist-GPCR-G-protein interaction, and the effect of this interaction on agonist efficacy. However, no consistent correlation has been proven for various binding-efficacy data, so several extensions of the model have been proposed. These extensions are of descriptive value but their validity cannot be verified by binding-efficacy correlations. Therefore, we developed a novel approach to validate the TCM and its extensions.
Methods:
We simulated the predictions of the TCM for relationships within binding parameters., According to the TCM, an increase in the difference between high and low agonist affinities, for a receptor (ie, greater KL/KH) should be accompanied by stability or an increase in the fraction, of receptors bound to the agonist with high affinity (RH). To validate these predictions we, performed ligand competition experiments for a set of β2-adrenergic receptor (AR) agonists and, analyzed the resulting binding data as well as data taken from relevant literature., Results: No smooth relationship exists between RH and KL/KH in our or others’ data, indicating, the insufficiency of the TCM and its extensions. We introduce the allosteric modulators model, as an alternative.
Conclusions:
To our knowledge, this is the first paper in which insufficiency of the TCM and its extensions based on binding data are shown, and the first in which the presence of allosteric modulators of ligand affinity is proven to be a necessity for explaining binding data at GPCRs.