Crystal structures of a stabilized β1-adrenoceptor bound to the biased agonists bucindolol and carvedilol

Structure. 2012 May 9;20(5):841-9. doi: 10.1016/j.str.2012.03.014.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Antagonists / chemistry
  • Adrenergic beta-Antagonists / metabolism*
  • Animals
  • Carbazoles / chemistry*
  • Carbazoles / metabolism
  • Carvedilol
  • Crystallography, X-Ray
  • Humans
  • Models, Molecular
  • Propanolamines / chemistry*
  • Propanolamines / metabolism
  • Receptors, Adrenergic, beta-1 / chemistry*
  • Receptors, Adrenergic, beta-1 / metabolism*
  • Turkeys


  • Adrenergic beta-Antagonists
  • Carbazoles
  • Propanolamines
  • Receptors, Adrenergic, beta-1
  • Carvedilol
  • bucindolol