Multiple ligand-specific conformations of the β2-adrenergic receptor
| Autor: | Arun K. Shukla, Seungkirl Ahn, Robert J. Lefkowitz, Alem W. Kahsai, Terrence G. Oas, Jin-Peng Sun, Sudarshan Rajagopal, Kunhong Xiao |
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| Rok vydání: | 2011 |
| Předmět: |
G protein-coupled receptor kinase
Chemistry Molecular Conformation Cell Biology Alpha-1B adrenergic receptor Ligands Mass Spectrometry Article Biochemistry Neurotransmitter receptor Functional selectivity Biophysics Enzyme-linked receptor Humans 5-HT5A receptor Receptors Adrenergic beta-2 Signal transduction Molecular Biology G protein-coupled receptor |
| Zdroj: | Nature Chemical Biology. 7:692-700 |
| ISSN: | 1552-4469 1552-4450 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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