Crystal Structures of a Stabilized β1-Adrenoceptor Bound to the Biased Agonists Bucindolol and Carvedilol

• Published in: Structure (London) 2012-05, Vol.20 (5), p.841-849
• Main Authors: Warne, Tony, Edwards, Patricia C., Leslie, Andrew G.W., Tate, Christopher G.
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Antagonists - chemistry; Adrenergic beta-Antagonists - metabolism; Animals; Carbazoles - chemistry; Carbazoles - metabolism; Crystallography, X-Ray; Humans; Models, Molecular; Propanolamines - chemistry; Propanolamines - metabolism; Receptors, Adrenergic, beta-1 - chemistry; Receptors, Adrenergic, beta-1 - metabolism; Turkeys
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2012.03.014

The β1-adrenoceptor (β1AR) 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/Gly3898.56 polymorphism of the human β1AR. 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 β1AR 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/Gly3898.56 polymorphism. [Display omitted] ► Structures of β1AR bound to the biased agonists bucindololol and carvedilol ► The biased agonists form unique contacts with β1AR not seen with other antagonists ► The structures explain the pharmacological differences in the Arg389Gly polymorphism