Figure 2.
Schematic of G Protein Coupled Receptor (GPCR). Panel A. Depiction of inactive receptor (left) and agonist-activated receptor (right). In the inactive state, the G protein-GDP bound subunit complex is bound to the receptor protein (left); whereas upon binding of agonist at the orthosteric site, the receptor is activated and the G protein subunits βγ dissociate from the GTP bound α subunit (right). Panel B illustrates binding of either competitive antagonist or negative allosteric modulator at orthosteric and allosteric sites respectively. Note that the receptor is not activated by either of these ligands. Panel C. Binding of a positive allosteric modulator, at an allosteric site. Note that this ligand does not activate the receptor in and of itself. Panel D. Constitutive activity is demonstrated on the left. The receptor is in an activated state, bound to the α subunit of the GDP-G protein complex, in the absence of agonist. Presumably in this state the receptor conformation is different than the agonist-receptor conformation, indicated by a difference in receptor shape and shading. Binding of an inverse agonist, at the orthosteric site of a constitutively active receptor causes a “disactivation” of constitutive activity, a presumed conformational change, and re-coupling of the G-protein subunits with the receptor. Note that the position of the G protein complex is shown bound to the receptor in a slightly different location to illustrate a different G protein-receptor conformational state, accommodating decreased basal activity consequent to inverse agonist binding.