TY - JOUR
T1 - A key agonist-induced conformational change in the cannabinoid receptor CB1 is blocked by the allosteric ligand Org 27569
AU - Fay, Jonathan F.
AU - Farrens, David L.
PY - 2012/9/28
Y1 - 2012/9/28
N2 - Allosteric ligands that modulate how G protein-coupled receptors respond to traditional orthosteric drugs are an exciting and rapidly expanding field of pharmacology. An allosteric ligand for the cannabinoid receptor CB1, Org 27569, exhibits an intriguing effect; it increases agonist binding, yet blocks agonist-induced CB1 signaling. Here we explored the mechanism behind this behavior, using a site-directed fluorescence labeling approach. Our results show that Org 27569 blocks conformational changes in CB1 that accompanyGprotein binding and/or activation, and thus inhibit formation of a fully active CB1 structure. The underlying mechanism behind this behavior is that simultaneous binding of Org 27569 produces a unique agonistbound conformation, one that may resemble an intermediate structure formed on the pathway to full receptor activation.
AB - Allosteric ligands that modulate how G protein-coupled receptors respond to traditional orthosteric drugs are an exciting and rapidly expanding field of pharmacology. An allosteric ligand for the cannabinoid receptor CB1, Org 27569, exhibits an intriguing effect; it increases agonist binding, yet blocks agonist-induced CB1 signaling. Here we explored the mechanism behind this behavior, using a site-directed fluorescence labeling approach. Our results show that Org 27569 blocks conformational changes in CB1 that accompanyGprotein binding and/or activation, and thus inhibit formation of a fully active CB1 structure. The underlying mechanism behind this behavior is that simultaneous binding of Org 27569 produces a unique agonistbound conformation, one that may resemble an intermediate structure formed on the pathway to full receptor activation.
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U2 - 10.1074/jbc.M112.352328
DO - 10.1074/jbc.M112.352328
M3 - Article
C2 - 22846992
AN - SCOPUS:84866952392
SN - 0021-9258
VL - 287
SP - 33873
EP - 33882
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 40
ER -