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Cell. 2013 Jan 31;152(3):532-42. doi: 10.1016/j.cell.2013.01.008.

The dynamic process of β(2)-adrenergic receptor activation.

Author information

1
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Abstract

G-protein-coupled receptors (GPCRs) can modulate diverse signaling pathways, often in a ligand-specific manner. The full range of functionally relevant GPCR conformations is poorly understood. Here, we use NMR spectroscopy to characterize the conformational dynamics of the transmembrane core of the β(2)-adrenergic receptor (β(2)AR), a prototypical GPCR. We labeled β(2)AR with (13)CH(3)ε-methionine and obtained HSQC spectra of unliganded receptor as well as receptor bound to an inverse agonist, an agonist, and a G-protein-mimetic nanobody. These studies provide evidence for conformational states not observed in crystal structures, as well as substantial conformational heterogeneity in agonist- and inverse-agonist-bound preparations. They also show that for β(2)AR, unlike rhodopsin, an agonist alone does not stabilize a fully active conformation, suggesting that the conformational link between the agonist-binding pocket and the G-protein-coupling surface is not rigid. The observed heterogeneity may be important for β(2)AR's ability to engage multiple signaling and regulatory proteins.

PMID:
23374348
PMCID:
PMC3586676
DOI:
10.1016/j.cell.2013.01.008
[Indexed for MEDLINE]
Free PMC Article

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