Functionally Different Agonists Induce Distinct Conformations in the G Protein Coupling Domain of the β2 Adrenergic Receptor

Pejman Ghanouni, Zygmunt Gryczynski, Jacqueline J. Steenhuis, Tae Weon Lee, David Farrens, Joseph R. Lakowicz, Brian K. Kobilka

Research output: Contribution to journalArticle

316 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)24433-24436
Number of pages4
JournalJournal of Biological Chemistry
Volume276
Issue number27
DOIs
StatePublished - Jul 6 2001

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GTP-Binding Proteins
Adrenergic Receptors
Conformations
G-Protein-Coupled Receptors
Ligands
Drug Discovery
Fluorophores
Fluorescence
Pharmaceutical Preparations
Protein Domains

ASJC Scopus subject areas

  • Biochemistry

Cite this

Functionally Different Agonists Induce Distinct Conformations in the G Protein Coupling Domain of the β2 Adrenergic Receptor. / Ghanouni, Pejman; Gryczynski, Zygmunt; Steenhuis, Jacqueline J.; Lee, Tae Weon; Farrens, David; Lakowicz, Joseph R.; Kobilka, Brian K.

In: Journal of Biological Chemistry, Vol. 276, No. 27, 06.07.2001, p. 24433-24436.

Research output: Contribution to journalArticle

Ghanouni, Pejman ; Gryczynski, Zygmunt ; Steenhuis, Jacqueline J. ; Lee, Tae Weon ; Farrens, David ; Lakowicz, Joseph R. ; Kobilka, Brian K. / Functionally Different Agonists Induce Distinct Conformations in the G Protein Coupling Domain of the β2 Adrenergic Receptor. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 27. pp. 24433-24436.
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