Crystal Structures of a Stabilized 尾₁-Adrenoceptor Bound to the Biased Agonists Bucindolol and Carvedilol

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• 作者：Tony Warne¹ ; Patricia&#160 ; C. Edwards¹ ; Andrew&#160 ; G.W. Leslie¹ ; Christopher&#160 ; G. Tate¹ ; ^{cgt@mrc-lmb.cam.ac.uk}
• 刊名：Structure
• 出版年：2012
• 期刊代码：143_09692126
• 类别：bio
• 出版时间：9 May, 2012
• 卷：20
• 期：5
• 页码：841-849
• 文件大小：1109 K

摘要

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Summary

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