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PMID: 22267580 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Biased signaling pathways in β2-adrenergic receptor characterized by 19F-NMR.

Science (New York, N.Y.) ·Vol. 335 ·No. 6072 ·2012-03-02 ·Pages 1106-10

Liu JJ, Horst R, Katritch V, Stevens RC, Wüthrich K

Abstract

Extracellular ligand binding to G protein-coupled receptors (GPCRs) modulates G protein and β-arrestin signaling by changing the conformational states of the cytoplasmic region of the receptor. Using site-specific (19)F-NMR (fluorine-19 nuclear magnetic resonance) labels in the β(2)-adrenergic receptor (β(2)AR) in complexes with various ligands, we observed that the cytoplasmic ends of helices VI and VII adopt two major conformational states. Changes in the NMR signals reveal that agonist binding primarily shifts the equilibrium toward the G protein-specific active state of helix VI. In contrast, β-arrestin-biased ligands predominantly impact the conformational states of helix VII. The selective effects of different ligands on the conformational equilibria involving helices VI and VII provide insights into the long-range structural plasticity of β(2)AR in partial and biased agonist signaling.

MeSH Terms
Adrenergic beta-2 Receptor Agonists/chemistry,metabolism,pharmacology Arrestins/metabolism Binding Sites Carbazoles/chemistry,metabolism,pharmacology Carvedilol Cytoplasm/chemistry Drug Partial Agonism Fluorine Isoetharine/chemistry,metabolism,pharmacology Isoproterenol/metabolism Ligands Models, Molecular Nuclear Magnetic Resonance, Biomolecular Propanolamines/chemistry,metabolism,pharmacology Protein Conformation Protein Structure, Secondary Receptors, Adrenergic, beta-2/chemistry,metabolism Signal Transduction Structure-Activity Relationship beta-Arrestins
Chemicals
Adrenergic beta-2 Receptor Agonists Arrestins Carbazoles Ligands Propanolamines Receptors, Adrenergic, beta-2 beta-Arrestins Carvedilol Fluorine Isoproterenol Isoetharine
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Liu Jeffrey J
Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Horst Reto
Katritch Vsevolod
Stevens Raymond C
Wüthrich Kurt
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.1215802
Published
2012-03-02
Epub
2012-00-19
Pages
1106-10
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC3292700
Subset
IM
Grants
NIGMS NIH HHS · P50 GM073197 · United States
NIGMS NIH HHS · P50 GM073197-08 · United States
NIGMS NIH HHS · U54 GM094618 · United States
NIGMS NIH HHS · U54 GM094618-02 · United States
Corrections
CommentIn
PMID: 22383838
External Links
PubMed source DOI: 10.1126/science.1215802 PMC Full Text View journal details
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