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PMID: 21889352 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural

Ligand-dependent perturbation of the conformational ensemble for the GPCR β2 adrenergic receptor revealed by HDX.

Structure (London, England : 1993) ·Vol. 19 ·No. 10 ·2011-10-12 ·Pages 1424-32

West GM, Chien EY, Katritch V, Gatchalian J, Chalmers MJ, Stevens RC, Griffin PR

Abstract

Mechanism of G protein-coupled receptor (GPCR) activation and their modulation by functionally distinct ligands remains elusive. Using the technique of amide hydrogen/deuterium exchange coupled with mass spectrometry, we examined the ligand-induced changes in conformational states and stability within the beta-2-adrenergic receptor (β(2)AR). Differential HDX reveals ligand-specific alterations in the energy landscape of the receptor's conformational ensemble. The inverse agonists timolol and carazolol were found to be most stabilizing even compared with the antagonist alprenolol, notably in intracellular regions where G proteins are proposed to bind, while the agonist isoproterenol induced the largest degree of conformational mobility. The partial agonist clenbuterol displayed conformational effects found in both the inverse agonists and the agonist. This study highlights the regional plasticity of the receptor and characterizes unique conformations spanning the entire receptor sequence stabilized by functionally selective ligands, all of which differ from the profile for the apo receptor.

MeSH Terms
Adrenergic beta-2 Receptor Agonists/metabolism Adrenergic beta-2 Receptor Antagonists/metabolism Alprenolol/metabolism Binding Sites Clenbuterol/metabolism Deuterium Exchange Measurement/methods Humans Hydrogen Bonding Ligands Mass Spectrometry Membranes/metabolism Peptides/metabolism Propanolamines/metabolism Protein Binding Protein Stability Protein Structure, Tertiary Receptors, Adrenergic, beta-2/chemistry,metabolism Timolol/metabolism
Chemicals
ADRB2 protein, human Adrenergic beta-2 Receptor Agonists Adrenergic beta-2 Receptor Antagonists Ligands Peptides Propanolamines Receptors, Adrenergic, beta-2 carazolol Timolol Alprenolol Clenbuterol
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
West Graham M
Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
Chien Ellen Y T
Katritch Vsevolod
Gatchalian Jovylyn
Chalmers Michael J
Stevens Raymond C
Griffin Patrick R
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Article Info
Journal
Structure (London, England : 1993)
Abbr.
Structure
ISSN
1878-4186
DOI
10.1016/j.str.2011.08.001
Published
2011-10-12
Epub
2011-00-01
Pages
1424-32
Language
English
Region
United States
NLM ID
101087697
PMCID
PMC3196059
Subset
IM
Grants
NIMH NIH HHS · U54 MH084512-03 · United States
NIGMS NIH HHS · U54 GM094618-02 · United States
NIMH NIH HHS · U54 MH084512 · United States
NIGMS NIH HHS · U54 GM094618-03 · United States
NIMH NIH HHS · U54-MH074404 · United States
NIGMS NIH HHS · U54 GM094618 · United States
NIGMS NIH HHS · R01 GM084041-03 · United States
NIGMS NIH HHS · R01 GM084041 · United States
NIGMS NIH HHS · U54-GM094618 · United States
NCRR NIH HHS · S10 RR027270 · United States
NIGMS NIH HHS · R01-GM084041 · United States
External Links
PubMed source DOI: 10.1016/j.str.2011.08.001 PMC Full Text View journal details
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