Multiple ligand-specific conformations of the β2-adrenergic receptor.
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.
Duke Scholars
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Related Subject Headings
- Receptors, Adrenergic, beta-2
- Molecular Conformation
- Mass Spectrometry
- Ligands
- Humans
- Biochemistry & Molecular Biology
- 3404 Medicinal and biomolecular chemistry
- 3101 Biochemistry and cell biology
- 0601 Biochemistry and Cell Biology
- 0304 Medicinal and Biomolecular Chemistry
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Receptors, Adrenergic, beta-2
- Molecular Conformation
- Mass Spectrometry
- Ligands
- Humans
- Biochemistry & Molecular Biology
- 3404 Medicinal and biomolecular chemistry
- 3101 Biochemistry and cell biology
- 0601 Biochemistry and Cell Biology
- 0304 Medicinal and Biomolecular Chemistry