@article {Seifert1218, author = {Roland Seifert and Katharina Wenzel-Seifert and Ulrik Gether and Brian K. Kobilka}, title = {Functional Differences between Full and Partial Agonists: Evidence for Ligand-Specific Receptor Conformations}, volume = {297}, number = {3}, pages = {1218--1226}, year = {2001}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {The interaction of an agonist-bound G-protein-coupled receptor (GPCR) with its cognate G-protein initiates a sequence of experimentally quantifiable changes in both the GPCR and G-protein. These include the release of GDP from Gα, the formation of a ternary complex between the nucleotide-free G-protein and the GPCR, which has a high affinity for agonist, followed by the binding of GTP to Gα, the dissociation of the GPCR/G-protein complex, and the hydrolysis of GTP. The efficacy of an agonist is a measure of its ability to activate this cascade. It has been proposed that efficacy reflects the ability of the agonist to stabilize the active state of the GPCR. We examined a series of β2-adrenoceptor (β2AR) agonists (weak partial agonists to full agonists) for their efficacy at promoting two different steps of the G-protein activation/deactivation cycle: stabilizing the ternary complex (high-affinity, GTP-sensitive agonist binding), and steady-state GTPase activity. We obtained results for the wild-type β2AR and a constitutively active mutant of the β2AR (β2ARCAM) using fusion proteins between the GPCRs and Gsα to facilitate GPCR/G-protein interactions. There was no correlation between efficacy of ligands in activating GTPase and their ability to stabilize the ternary complex at β2ARCAM. Our results suggest that the GPCR state that optimally promotes the GDP release and GTP binding is different from the GPCR state that stabilizes the ternary complex. By strongly stabilizing the ternary complex, certain partial agonists may reduce the rate of G-protein turnover relative to a full agonist. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/297/3/1218}, eprint = {https://jpet.aspetjournals.org/content/297/3/1218.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }