Crystal structures of a stabilized ?1-adrenoceptor bound to the biased agonists bucindolol and carvedilol.

ABSTRACT: The ?(1)-adrenoceptor (?(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 ?(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 ?(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.

SUBMITTER: Warne T 

PROVIDER: S-EPMC3384003 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature