Figure 11.

Simplified description of family A GPCR binding sites in the antagonist and agonist conformational states. Antagonists bind to both H-bonding and lipophilic subsites in a more open form of the orthosteric pocket of the receptor. NAMs are proposed to occupy an allosteric pocket at the entrance to the receptor adjacent to ECL2. Agonists trigger a change in receptor conformation on binding to the antagonist state in which the volume of the binding site decreases and new polar interactions are formed deep inside the pocket close to the toggle switch W6.48. PAMs are proposed to stabilize the agonist state by binding to the allosteric pocket in an alternative conformation.