Structure of the Adenosine A2A Receptor in Complex with ZM241385 and the Xanthines XAC and Caffeine

被引：429

作者：

Dore, Andrew S. ^{[1
]}

Robertson, Nathan ^{[1
]}

Errey, James C. ^{[1
]}

Ng, Irene ^{[1
]}

Hollenstein, Kaspar ^{[1
]}

Tehan, Ben ^{[1
]}

Hurrell, Edward ^{[1
]}

Bennett, Kirstie ^{[1
]}

Congreve, Miles ^{[1
]}

Magnani, Francesca ^{[2
]}

Tate, Christopher G. ^{[2
]}

Weir, Malcolm ^{[1
]}

Marshall, Fiona H. ^{[1
]}

机构：

[1] Heptares Therapeut Ltd, Welwyn Garden City AL7 3AX, Herts, England

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

来源：

STRUCTURE | 2011年 / 19卷 / 09期

基金：

英国医学研究理事会;

关键词：

PROTEIN-COUPLED RECEPTORS; CRYSTAL-STRUCTURE; GPCR; AGONIST; THERMOSTABILIZATION; ANTAGONIST; FEATURES; DOMAINS;

D O I：

10.1016/j.str.2011.06.014

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：

Methylxanthines, including caffeine and theophylline, are among the most widely consumed stimulant drugs in the world. These effects are mediated primarily via blockade of adenosine receptors. Xanthine analogs with improved properties have been developed as potential treatments for diseases such as Parkinson's disease. Here we report the structures of a thermostabilized adenosine A(2A) receptor in complex with the xanthines xanthine amine congener and caffeine, as well as the A(2A) selective inverse agonist ZM241385. The receptor is crystallized in the inactive state conformation as defined by the presence of a salt bridge known as the ionic lock. The complete third intracellular loop, responsible for G protein coupling, is visible consisting of extended helices 5 and 6. The structures provide new insight into the features that define the ligand binding pocket of the adenosine receptor for ligands of diverse chemotypes as well as the cytoplasmic regions that interact with signal transduction proteins.

引用

页码：1283 / 1293

页数：11

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