Insights into signaling from the beta2-adrenergic receptor structure.
With more than 800 members, the G protein-coupled receptor family constitutes the largest group of membrane proteins involved in signal transduction. Until the end of last year, high-resolution three-dimensional structures were available for only one of them--the light receptor rhodopsin. Recently the structure of the beta(2)-adrenergic receptor has been obtained, and it revealed interesting differences with the structure of rhodopsin. Analyses of these differences raise important questions about the binding modes of diffusible ligands in the receptor and allow formulation of testable hypotheses about the structural determinants linking drug binding to specific signaling responses. The three-dimensional structure derived from the beta(2)-adrenergic receptor crystal has been used to virtually dock ligands with distinct activities. The different binding modes of these ligands, which correlated with their reported efficacy profiles, suggest that it could be possible to predict the structural determinants of drug signaling efficacies.
Department of Biochemistry, Institute for Research in Immunology and Cancer, Groupe de Recherche Universitaire sur le Médicament, Université de Montréal, CP 6128 Succursale Centre-Ville, Montréal, Québec H3C 3J7, Canada.
Martin
M
Audet
Michel
M
Bouvier
D000322:Adrenergic Agonists / Q000494:pharmacology; D018674:Adrenergic Antagonists / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014961:X-Ray Diffraction
D000322:Adrenergic Agonists; D018674:Adrenergic Antagonists; D008024:Ligands; D018343:Receptors, Adrenergic, beta-2