title: Crystal structures of a stabilized β1-adrenoceptor bound to the biased agonists bucindolol and carvedilol.
abstract: The β(1)-adrenoceptor (β(1)AR) is the site of action of beta blockers used in the treatment of cardiac-related illnesses. Two beta blockers, carvedilol and bucindolol, show distinctive activities compared to other beta blockers and have been proposed as treatments tailored to the Arg/Gly389(8.56) polymorphism of the human β(1)AR. Both carvedilol and bucindolol are classified as biased agonists, because they stimulate G protein-independent signaling, while acting as either inverse or partial agonists of the G protein pathway. We have determined the crystal structures of a thermostabilized avian β(1)AR mutant bound to bucindolol and to carvedilol at 3.2 and 2.3 Å resolution, respectively. In comparison to other beta blockers, bucindolol and carvedilol interact with additional residues, in extracellular loop 2 and transmembrane helix 7, which may promote G protein-independent signaling. The structures also suggest that there may be a structural explanation for the pharmacological differences arising from the Arg/Gly389(8.56) polymorphism.
authors.affiliation: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
authors.forename: Tony
authors.initials: T
authors.lastname: Warne
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Edwards
authors.forename: Andrew G W
authors.initials: AG
authors.lastname: Leslie
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Tate
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002227:Carbazoles / Q000737:chemistry* / Q000378:metabolism; D000077261:Carvedilol; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D011412:Propanolamines / Q000737:chemistry* / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000737:chemistry* / Q000378:metabolism*; D014422:Turkeys
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; D000077261:Carvedilol; C024307:bucindolol