Multiple ligand-specific conformations of the β2-adrenergic receptor.
By Alem W. Kahsai, Kunhong Xiao, S. Rajagopal, Seungkirl Ahn, A. Shukla, Jin-peng Sun, Terrence G. Oas, R. J. Lefkowitz. 2011
253 citations recorded by the source corpus.
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 β2-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.
Subfields: Animal Science and Zoology, Molecular Biology, Spectroscopy, Computational Biology & Bioinformatics
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In Molecular Biology
- Éric Reiter
- Seungkirl Ahn
- A. Shukla
- R. J. Lefkowitz
- Glaucius Oliva
- L. Ferreira
- Ricardo N Dos Santos
- Adriano Defini Andricopulo
In Spectroscopy
In Computational Biology & Bioinformatics
Citations in the corpus
- Molecular Docking and Structure-Based Drug Design Strategies (2015, background): “Structural descriptions of ligand-receptor complexes are useful for the investigation of binding conformations, characterization of key intermolecular interactions, characterization of unknown binding sites, mechanistic studies and the elucidation of ligand-induced conformational changes [17].”
- Molecular Mechanism of β-Arrestin-Biased Agonism at Seven-Transmembrane Receptors (2011, methodology): “, negative log of relaxation times), measured at each of the nine cysteines or lysines upon receptor binding with nine different ligands, were plotted in a heat map (47).”