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Multiple ligand-specific conformations of the ?2-adrenergic receptor.


ABSTRACT: 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 ?-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 ?(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.

SUBMITTER: Kahsai AW 

PROVIDER: S-EPMC3404607 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Multiple ligand-specific conformations of the β2-adrenergic receptor.

Kahsai Alem W AW   Xiao Kunhong K   Rajagopal Sudarshan S   Ahn Seungkirl S   Shukla Arun K AK   Sun Jinpeng J   Oas Terrence G TG   Lefkowitz Robert J RJ  

Nature chemical biology 20110821 10


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 largel  ...[more]

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