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Publication Abstract from PubMed

The beta(1)-adrenoceptor (beta(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 beta(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 beta(1)AR mutant bound to bucindolol and to carvedilol at 3.2 and 2.3 A 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.

Crystal Structures of a Stabilized beta(1)-Adrenoceptor Bound to the Biased Agonists Bucindolol and Carvedilol.,Warne T, Edwards PC, Leslie AG, Tate CG Structure. 2012 May 9;20(5):841-9. PMID:22579251^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.