Cell
Volume 161, Issue 5, 21 May 2015, Pages 1101-1111
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Article
Structural Insights into the Dynamic Process of β2-Adrenergic Receptor Signaling

https://doi.org/10.1016/j.cell.2015.04.043Get rights and content
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Highlights

  • Two inactive states predominate in unliganded and antagonist-bound β2AR

  • Agonists increase structural heterogeneity in β2AR cytoplasmic domains

  • The agonist-binding pocket and cytoplasmic surface have weak allosteric coupling

  • Complete receptor activation requires G protein or a mimetic nanobody

Summary

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 19F-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.

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