TY - JOUR
T1 - Functionally Different Agonists Induce Distinct Conformations in the G Protein Coupling Domain of the β2 Adrenergic Receptor
AU - Ghanouni, Pejman
AU - Gryczynski, Zygmunt
AU - Steenhuis, Jacqueline J.
AU - Lee, Tae Weon
AU - Farrens, David L.
AU - Lakowicz, Joseph R.
AU - Kobilka, Brian K.
PY - 2001/7/6
Y1 - 2001/7/6
N2 - G protein-coupled receptors represent the largest class of drug discovery targets. Drugs that activate G protein-coupled receptors are classified as either agonists or partial agonists. To study the mechanism whereby these different classes of activating ligands modulate receptor function, we directly monitored ligand-induced conformational changes in the G protein-coupling domain of the β2 adrenergic receptor. Fluorescence lifetime analysis of a reporter fluorophore covalently attached to this domain revealed that, in the absence of ligands, this domain oscillates around a single detectable conformation. Binding to an antagonist does not change this conformation but does reduce the flexibility of the domain. However, when the β2 adrenergic receptor is bound to a full agonist, the G protein coupling domain exists in two distinct conformations. Moreover, the conformations induced by a full agonist can be distinguished from those induced by partial agonists. These results provide new insight into the structural consequence of antagonist binding and the basis of agonism and partial agonism.
AB - G protein-coupled receptors represent the largest class of drug discovery targets. Drugs that activate G protein-coupled receptors are classified as either agonists or partial agonists. To study the mechanism whereby these different classes of activating ligands modulate receptor function, we directly monitored ligand-induced conformational changes in the G protein-coupling domain of the β2 adrenergic receptor. Fluorescence lifetime analysis of a reporter fluorophore covalently attached to this domain revealed that, in the absence of ligands, this domain oscillates around a single detectable conformation. Binding to an antagonist does not change this conformation but does reduce the flexibility of the domain. However, when the β2 adrenergic receptor is bound to a full agonist, the G protein coupling domain exists in two distinct conformations. Moreover, the conformations induced by a full agonist can be distinguished from those induced by partial agonists. These results provide new insight into the structural consequence of antagonist binding and the basis of agonism and partial agonism.
UR - http://www.scopus.com/inward/record.url?scp=0035816704&partnerID=8YFLogxK
U2 - 10.1074/jbc.C100162200
DO - 10.1074/jbc.C100162200
M3 - Article
C2 - 11320077
AN - SCOPUS:0035816704
SN - 0021-9258
VL - 276
SP - 24433
EP - 24436
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 27
ER -