Ligand-Induced Conformational Changes of the beta_(2) Adrenoceptor Elucidated by Structural Proteomics

摘要

Seven transmembrane receptors (7TMRs) including beta2-adrenergic receptor (beta_(2)AR) elicit various physiological responses through their interaction with structurally different ligands by promoting distinct conformational changes. To understand the detailed ligand-specific conformational changes that occur upon ligand binding to the beta2AR and their interplay with biological functions, we developed a quantitative proteomics approach that involves chemical modifications at cysteine and lysine side-chains using specific isotope-labeled reagents followed by mass-spectrometry analysis. Our results show that different ligands with varying efficacies for several signaling pathways produce distinctly different pattern in the extent of reagent accessibility at different residues. From these we deduced at least three distinct receptor conformations. In summary, the results from this approach provide new insights into the global ligand-induced conformational changes of beta_(2)AR.