Download MendeleyCrystal Structures of a Stabilized Beta1-Adrenoceptor Bound to the Biased Agonists Bucindolol and Carvedilol
Warne, T., Edwards, P.C., Leslie, A.G., Tate, C.G.(2012) Structure 20: 841
- PubMed: 22579251
- DOI: https://doi.org/10.1016/j.str.2012.03.014
- Primary Citation of Related Structures:
4AMI, 4AMJ - PubMed 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 ? 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.
Organizational Affiliation:
MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
