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Nat Chem Biol. 2011 Aug 21;7(10):692-700. doi: 10.1038/nchembio.634.

Multiple ligand-specific conformations of the β2-adrenergic receptor.

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1
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.

Abstract

Seven-transmembrane receptors (7TMRs), also called G protein-coupled receptors (GPCRs), represent the largest class of drug targets, and they can signal through several distinct mechanisms including those mediated by G proteins and the multifunctional adaptor proteins β-arrestins. Moreover, several receptor ligands with differential efficacies toward these distinct signaling pathways have been identified. However, the structural basis and mechanism underlying this 'biased agonism' remains largely unknown. Here, we develop a quantitative mass spectrometry strategy that measures specific reactivities of individual side chains to investigate dynamic conformational changes in the β(2)-adrenergic receptor occupied by nine functionally distinct ligands. Unexpectedly, only a minority of residues showed reactivity patterns consistent with classical agonism, whereas the majority showed distinct patterns of reactivity even between functionally similar ligands. These findings demonstrate, contrary to two-state models for receptor activity, that there is significant variability in receptor conformations induced by different ligands, which has significant implications for the design of new therapeutic agents.

PMID:
21857662
PMCID:
PMC3404607
DOI:
10.1038/nchembio.634
[Indexed for MEDLINE]
Free PMC Article
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