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Cell. 2015 May 21;161(5):1101-1111. doi: 10.1016/j.cell.2015.04.043. Epub 2015 May 14.

Structural Insights into the Dynamic Process of β2-Adrenergic Receptor Signaling.

Author information

1
Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA.
2
Department of Chemistry, University of Toronto, UTM, 3359 Mississauga Road North, Mississauga, Ontario L5L 1C6, Canada.
3
Jules Stein Eye Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095-7008, USA.
4
Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA. Electronic address: kobilka@stanford.edu.

Erratum in

  • Cell. 2015 Sep 10;162(6):1431.

Abstract

G-protein-coupled receptors (GPCRs) transduce signals from the extracellular environment to intracellular proteins. To gain structural insight into the regulation of receptor cytoplasmic conformations by extracellular ligands during signaling, we examine the structural dynamics of the cytoplasmic domain of the β2-adrenergic receptor (β2AR) using (19)F-fluorine NMR and double electron-electron resonance spectroscopy. These studies show that unliganded and inverse-agonist-bound β2AR exists predominantly in two inactive conformations that exchange within hundreds of microseconds. Although agonists shift the equilibrium toward a conformation capable of engaging cytoplasmic G proteins, they do so incompletely, resulting in increased conformational heterogeneity and the coexistence of inactive, intermediate, and active states. Complete transition to the active conformation requires subsequent interaction with a G protein or an intracellular G protein mimetic. These studies demonstrate a loose allosteric coupling of the agonist-binding site and G-protein-coupling interface that may generally be responsible for the complex signaling behavior observed for many GPCRs.

PMID:
25981665
PMCID:
PMC4441853
DOI:
10.1016/j.cell.2015.04.043
[Indexed for MEDLINE]
Free PMC Article

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