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

Publication ,  Journal Article
Kahsai, AW; Xiao, K; Rajagopal, S; Ahn, S; Shukla, AK; Sun, J; Oas, TG; Lefkowitz, RJ
Published in: Nat Chem Biol
August 21, 2011

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.

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Published In

Nat Chem Biol

DOI

EISSN

1552-4469

Publication Date

August 21, 2011

Volume

7

Issue

10

Start / End Page

692 / 700

Location

United States

Related Subject Headings

  • Receptors, Adrenergic, beta-2
  • Molecular Conformation
  • Mass Spectrometry
  • Ligands
  • Humans
  • Biochemistry & Molecular Biology
  • 3404 Medicinal and biomolecular chemistry
  • 3101 Biochemistry and cell biology
  • 0601 Biochemistry and Cell Biology
  • 0304 Medicinal and Biomolecular Chemistry
 

Citation

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Kahsai, A. W., Xiao, K., Rajagopal, S., Ahn, S., Shukla, A. K., Sun, J., … Lefkowitz, R. J. (2011). Multiple ligand-specific conformations of the β2-adrenergic receptor. Nat Chem Biol, 7(10), 692–700. https://doi.org/10.1038/nchembio.634
Kahsai, Alem W., Kunhong Xiao, Sudarshan Rajagopal, Seungkirl Ahn, Arun K. Shukla, Jinpeng Sun, Terrence G. Oas, and Robert J. Lefkowitz. “Multiple ligand-specific conformations of the β2-adrenergic receptor.Nat Chem Biol 7, no. 10 (August 21, 2011): 692–700. https://doi.org/10.1038/nchembio.634.
Kahsai AW, Xiao K, Rajagopal S, Ahn S, Shukla AK, Sun J, et al. Multiple ligand-specific conformations of the β2-adrenergic receptor. Nat Chem Biol. 2011 Aug 21;7(10):692–700.
Kahsai, Alem W., et al. “Multiple ligand-specific conformations of the β2-adrenergic receptor.Nat Chem Biol, vol. 7, no. 10, Aug. 2011, pp. 692–700. Pubmed, doi:10.1038/nchembio.634.
Kahsai AW, Xiao K, Rajagopal S, Ahn S, Shukla AK, Sun J, Oas TG, Lefkowitz RJ. Multiple ligand-specific conformations of the β2-adrenergic receptor. Nat Chem Biol. 2011 Aug 21;7(10):692–700.

Published In

Nat Chem Biol

DOI

EISSN

1552-4469

Publication Date

August 21, 2011

Volume

7

Issue

10

Start / End Page

692 / 700

Location

United States

Related Subject Headings

  • Receptors, Adrenergic, beta-2
  • Molecular Conformation
  • Mass Spectrometry
  • Ligands
  • Humans
  • Biochemistry & Molecular Biology
  • 3404 Medicinal and biomolecular chemistry
  • 3101 Biochemistry and cell biology
  • 0601 Biochemistry and Cell Biology
  • 0304 Medicinal and Biomolecular Chemistry