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

Author Robert J. Lefkowitz Medicine, Cardiology

Author Alem W Kahsai Medicine, Cardiology

Author Kunhong Xiao Medicine, Cardiology

Author Sudarshan Rajagopal Medicine, Cardiology

Author Seungkirl Ahn Medicine, Cardiology

Author Terrence Gilbert Oas Biochemistry