FIGURE 11.

EC-3 loop conformations (and interactions) of various states of the CB₁ receptor. The view is from lipid looking toward TMH3 with TMH1, the EC-1 loop, and the EC-2 loop omitted for clarity. A, EC-3 loop conformations of the CB₁ receptor in its R* conformation. CP55,940 is shown in cyan, contoured at its van der Waals radii. D2.63¹⁷⁶ and Lys-373 (orange tube) are shown forming a hydrogen bond (yellow dashes). We have recently reported (25) that, upon activation, this interaction promotes an EC-3 loop conformation that is pulled across the extracellular face of the CB₁ receptor. B, EC-3 loop conformation of the CP55,940 (cyan, van der Waals)-CB₁ complex, in the presence of ORG27569 (lime green, van der Waals). D2.63¹⁷⁶ and Lys-373 shown here in orange. This image shows ORG27569 sterically blocking D2.63¹⁷⁶ and Lys-373 from forming a hydrogen bond, preventing this interaction from promoting an active conformation of the EC-3 loop. This steric hindrance of the D2.63¹⁷⁶ and Lys-373 (and indeed, the EC-3 loop in general) may provide an additional reason for ORG27569 antagonism of CP55,940 efficacy.