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Papers In Press, published online ahead of print April 24, 2001
J. Biol. Chem, 10.1074/jbc.C100162200
Submitted on April 4, 2001
Revised on April 24, 2001
Accepted on April 24, 2001
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305
Corresponding Author: kobilka{at}stanford.edu
G protein coupled receptors (GPCR) represent the largest class of drug discovery targets. Drugs that activate GPCRs 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 beta 2 adrenergic receptor (b2AR). 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 domain's flexibility. However, when the b2AR 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.
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