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

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 ?(2)-adrenergic receptor (?(2)AR), a prototypical GPCR. We labeled ?(2)AR with (13)CH(3)?-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 ?(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 ?(2)AR's ability to engage multiple signaling and regulatory proteins.

SUBMITTER: Nygaard R 

PROVIDER: S-EPMC3586676 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature