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PMID: 22748765 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Ligand-specific interactions modulate kinetic, energetic, and mechanical properties of the human β2 adrenergic receptor.

Structure (London, England : 1993) ·Vol. 20 ·No. 8 ·2012-08-08 ·Pages 1391-402

Zocher M, Fung JJ, Kobilka BK, Müller DJ

Abstract

G protein-coupled receptors (GPCRs) are a class of versatile proteins that transduce signals across membranes. Extracellular stimuli induce inter- and intramolecular interactions that change the functional state of GPCRs and activate intracellular messenger molecules. How these interactions are established and how they modulate the functional state of GPCRs remain to be understood. We used dynamic single-molecule force spectroscopy to investigate how ligand binding modulates the energy landscape of the human β2 adrenergic receptor (β2 AR). Five different ligands representing either agonists, inverse agonists or neutral antagonists established a complex network of interactions that tuned the kinetic, energetic, and mechanical properties of functionally important structural regions of β2 AR. These interactions were specific to the efficacy profile of the ligands investigated and suggest that the functional modulation of GPCRs follows structurally well-defined interaction patterns.

MeSH Terms
Adrenergic beta-2 Receptor Agonists/chemistry Adrenergic beta-2 Receptor Antagonists/chemistry Alprenolol/chemistry Amino Acid Sequence Binding Sites Biomechanical Phenomena Elasticity Epinephrine/chemistry Humans Kinetics Ligands Liposomes/chemistry Microscopy, Atomic Force Models, Molecular Molecular Sequence Data Propanolamines/chemistry Protein Binding Protein Stability Protein Structure, Secondary Protein Structure, Tertiary Protein Unfolding Receptors, Adrenergic, beta-2/chemistry Thermodynamics
Chemicals
Adrenergic beta-2 Receptor Agonists Adrenergic beta-2 Receptor Antagonists Ligands Liposomes Propanolamines Receptors, Adrenergic, beta-2 carazolol Alprenolol Epinephrine
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Zocher Michael
Department of Biosystems Science and Engineering, ETH Zürich, Mattenstr. 26, 4058 Basel, Switzerland.
Fung Juan J
Kobilka Brian K
Müller Daniel J
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Article Info
Journal
Structure (London, England : 1993)
Abbr.
Structure
ISSN
1878-4186
DOI
10.1016/j.str.2012.05.010
Published
2012-08-08
Epub
2012-00-28
Pages
1391-402
Language
English
Region
United States
NLM ID
101087697
PMCID
PMC4506644
Subset
IM
Grants
NINDS NIH HHS · R01 NS028471 · United States
Corrections
CommentIn
PMID: 22884104
External Links
PubMed source DOI: 10.1016/j.str.2012.05.010 PMC Full Text View journal details
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