Ligand-Specific Interactions Modulate Kinetic, Energetic, and Mechanical Properties of the Human β2 Adrenergic Receptor

• Published in: Structure (London) Vol. 20; no. 8; pp. 1391 - 1402
• Main Authors: Zocher, Michael, Fung, Juan J., Kobilka, Brian K., Müller, Daniel J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.08.2012
• Subjects: 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
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2012.05.010

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 (β2AR). 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 β2AR. 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. [Display omitted] ► We localize molecular interactions of the human β2 adrenergic receptor (β2AR) ► We characterize how different ligands modulate these interactions ► Mapping interaction networks established by different ligands binding to β2AR ► Ligands modulate specific structural regions of β2AR Zocher et al. use single molecule approaches to quantify to which extent five different ligands change the energy landscape of human β2AR. Ligand binding changes kinetic, energetic, and mechanical properties of β2AR, suggesting that the functional modulation of GPCRs follows well-defined interaction patterns.