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Multiple ligand-specific conformations of the β2-adrenergic receptor

2011; Nature Portfolio; Volume: 7; Issue: 10 Linguagem: Inglês

10.1038/nchembio.634

1552-4469

Alem W. Kahsai, Kunhong Xiao, Sudarshan Rajagopal, Seungkirl Ahn, Arun K. Shukla, Jin‐Peng Sun, Terrence G. Oas, Robert J. Lefkowitz,

Pharmacological Effects and Assays

A quantitative covalent labeling strategy reveals that multiple ligand-specific conformational states are present in the G protein–coupled β2-adrenergic receptor. Their existence may underlie 'biased agonism', which describes the differential abilities of agonists to activate distinct signaling mechanisms downstream of GPCRs. 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.