FIGURE 4.

The two energetically most favorable binding modes of the allosteric modulator BMS-986187 – colored yellow and cyan – at the DOP receptor in complex with the orthosteric ligand SNC-80, which is colored in gray. In sticks are the DOP receptor residues in the putative DOP allosteric site used in mutagenesis experiments to help validate the most likely binding mode. The plots to the right show the effect of mutations on the affinity of the allosteric ligand (top right), the induced changes in affinity of the orthosteric ligand (middle plot), and the changes in orthosteric ligand efficacy when the allosteric ligand is bound (bottom right). The experimental data support the predicted BMS-986187 binding mode in cyan color as the most favorable one. Astars indicate the statistical significance levels as given by Dunnet’s test p values (^∗p < 0.05, ^∗∗p < 0.01, and ^∗∗∗p < 0.001).