Crystal Structures of a Stabilized β1-Adrenoceptor Bound to the Biased Agonists Bucindolol and Carvedilol

被引：187

作者：

Warne, Tony ^{[1
]}

Edwards, Patricia C. ^{[1
]}

Leslie, Andrew G. W. ^{[1
]}

Tate, Christopher G. ^{[1
]}

机构：

[1] MRC Lab Mol Biol, Cambridge CB2 0QH, England

来源：

STRUCTURE | 2012年 / 20卷 / 05期

基金：

英国医学研究理事会; 英国生物技术与生命科学研究理事会;

关键词：

PROTEIN-COUPLED RECEPTOR; BETA-ADRENERGIC-RECEPTORS; 7-TRANSMEMBRANE RECEPTORS; BETA-1-ADRENERGIC RECEPTOR; ARRESTIN; CRYSTALLIZATION; ADRENOCEPTOR; POLYMORPHISM; ACTIVATION; PHOSPHORYLATION;

D O I：

10.1016/j.str.2012.03.014

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 angstrom 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.

引用

页码：841 / 849

页数：9

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