Saturation of allosteric effect due to full occupancy of the allosteric site. (A) Schematic diagram of two binding sites on the receptor, one for the natural agonist (orthosteric site) and the other for the allosteric modulator. (B) Limited antagonism of agonist responses by a NAM. The response in the presence of increasing concentrations of NAM B is shown in red moving to the right as the concentration of B increases ([B]/K_B = 3, 10, 30, 100, 300). Black dotted lines represent analogous dose response curves in the presence of an orthosteric competitive antagonist at the same concentrations. Arrows show the respective dose ratios for each concentration.

(A) Dose-response curve in vivo to a natural agonist in black; same curve in the presence of PAM1 (which produces a 50-fold sensitization to natural agonism) in red. Blue vertical arrow indicates the in vivo effect of PAM₁ (above toxicity level). (B) Red curve is for a different PAM (PAM₂, which produces a 5-fold sensitization); blue arrows show that the maximal effect of PAM₂ never will attain toxicity. In this case, it is assumed that the basal physiologic response is produced by 1 μM natural agonist.

Effect of an orthosteric (alvameline) and allosteric (BQCA) partial agonist on acetylcholine responses. (A) Schematic diagram of the relative binding geography of BQCA, acetylcholine (ACh), and alvameline. (B) Concentration-response curves for IP1 production mediated through muscarinic m1 receptors in CHO cells by ACh in the absence (filled circles) and presence of alvameline (100 μM, open circles) and BQCA (10 μM, open triangles) dotted line curve. Assuming a basal muscarinic receptor tone in vivo of 46%, alvameline would produce an inhibition of basal tone and BQCA an augmentation of basal tone. Data for panel (B) simulation from Bdioui et al. (2018).

Schematic diagram demonstrating three separate functional allosteric binding sites on GPR40. Binding locations from Wang et al. (2021).

Schematic diagram of two proteins binding at multiple loci; an orthosteric ligand can interfere with only one of those, whereas an allosteric ligand producing a global change in conformation may interfere with more than one site.

Selective inhibition of HV-1 entry over CCL3L1-induced CCR5 internalization by the allosteric modulator TAK652. Data from Muniz-Medina et al. (2009).

Bar graph shows potentiation of EC₅₀ values of GLP-1 receptor agonists produced by NOVO2. With the exception of exendin-4, peptide fragments are all natural agonists of the receptor, with GLP-1(7-36)NH₂ being the most important. Although NOVO2 produces a powerful potentiation of the minor agonist oxyntomodulin, the effects on the most relevant agonist are mild. Data from Koole et al. (2010).