4AMJ

Turkey beta1 adrenergic receptor with stabilising mutations and bound biased agonist carvedilol

Summary for 4AMJ

• Entry DOI: 10.2210/pdb4amj/pdb
• Related: 1DEP 2VT4 2Y00 2Y01 2Y02 2Y03 2Y04 2YCW 2YCX 2YCY 2YCZ 4AMI
• Descriptor: BETA-1 ADRENERGIC RECEPTOR, (2S)-1-(8H-CARBAZOL-4-YLOXY)-3-[2-(2-METHOXYPHENOXY)ETHYLAMINO]PROPAN-2-OL, SODIUM ION, ... (5 entities in total)
• Functional Keywords: membrane protein, 7tmr beta1-adrenoceptor, stabilising mutations, biased agonist
• Biological source: MELEAGRIS GALLOPAVO (TURKEY)
• Total number of polymer chains: 2
• Total formula weight: 77294.35

Authors

Warne, T.,Edwards, P.C.,Leslie, A.G.,Tate, C.G. (deposition date: 2012-03-12, release date: 2012-05-23, Last modification date: 2024-11-06)

Primary citation

Warne, T.,Edwards, P.C.,Leslie, A.G.,Tate, C.G.
Crystal Structures of a Stabilized Beta1-Adrenoceptor Bound to the Biased Agonists Bucindolol and Carvedilol
Structure, 20:841-, 2012

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 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.

PubMed: 22579251
DOI: 10.1016/J.STR.2012.03.014

Experimental method

X-RAY DIFFRACTION (2.3 Å)