The dynamic process of β2-adrenergic receptor activation

Rie Nygaard, Yaozhong Zou, Ron O. Dror, Thomas J. Mildorf, Daniel H Arlow, Aashish Manglik, Albert C Pan, Corey W. Liu, Juan José Fung, Michael P. Bokoch, Foon Sun Thian, Tong Sun Kobilka, David E Shaw, Luciano Mueller, R. Scott Prosser, Brian K. Kobilka

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528 Citations (Scopus)

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 β2-adrenergic receptor (β2AR), a prototypical GPCR. We labeled β2AR with 13CH3ε- 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 2AR, 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 β2AR's ability to engage multiple signaling and regulatory proteins.

Original languageEnglish
Pages (from-to)532-542
Number of pages11
JournalCell
Volume152
Issue number3
DOIs
Publication statusPublished - 31 Jan 2013
Externally publishedYes

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