Abstract
The description of the allosteric modification of receptors to affect changes in their function requires a model that considers the effects of the modulator on both agonist affinity and efficacy. A model is presented which describes changes in affinity in terms of the constant α (ratio of affinity in the presence vs the absence of modulator) and also the constant ξ (ratio of intrinsic efficacy of the agonist in the presence vs absence of modulator). This allows independent effects of both affinity and efficacy and allows the modeling of any change in the dose-response curve to an agonist after treatment with modulator. Examples are given where this type of model can predict effects of modulators that reduce efficacy but actually increase affinity of agonist (i.e. ifenprodil) and also of modulators that block the action of some agonists (the CXCR4 agonist SDF-1α by the antagonist AMD3100) but not others for the same receptor (SDF-1α peptide fragments RSVM and ASLW). ‘All models are wrong…but some are useful…’anonymous environmental scientist
Highlights
Heptahelical receptors are nature’s prototype allosteric protein
This paper will discuss the allosteric nature of these receptors, the mechanisms by which small molecules can influence large protein tertiary structure, and the models used to describe and predict these effects
It can be seen from the foregoing discussion that an allosteric modulator can alter the affinity and efficacy of a probe molecule for a receptor; as noted previously, the receptor essentially can become a different receptor with respect to that probe
Summary
Heptahelical ( referred to as seven transmembrane, 7TM, G-protein coupled) receptors are nature’s prototype allosteric protein. If =10, the affinity of the receptor for the probe is increased 10-fold when the modulator is bound This model, when combined with the Operational model for receptor function [4], yields a useful model to describe allosteric functional effects (see Fig. 2) [25,26]. This theory predicts that there is a positive correlation between ligand affinity and efficacy and, this was observed in a simulation [28] It can be seen from the foregoing discussion that an allosteric modulator can alter the affinity and efficacy of a probe molecule (agonist) for a receptor; as noted previously, the receptor essentially can become a different receptor with respect to that probe. Such antagonists will reduce but not completely block physiological response, a unique effect that may be therapeutically useful in certain pathological conditions
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