title: Multiple ligand-specific conformations of the β2-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 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.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Alem W
authors.initials: AW
authors.lastname: Kahsai
authors.forename: Kunhong
authors.initials: K
authors.lastname: Xiao
authors.forename: Sudarshan
authors.initials: S
authors.lastname: Rajagopal
authors.forename: Seungkirl
authors.initials: S
authors.lastname: Ahn
authors.forename: Arun K
authors.initials: AK
authors.lastname: Shukla
authors.forename: Jinpeng
authors.initials: J
authors.lastname: Sun
authors.forename: Terrence G
authors.initials: TG
authors.lastname: Oas
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lefkowitz
mesh_terms: D006801:Humans; D008024:Ligands; D013058:Mass Spectrometry; D008968:Molecular Conformation; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008024:Ligands; D018343:Receptors, Adrenergic, beta-2