Structure
Volume 19, Issue 9, 7 September 2011, Pages 1283-1293
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Article
Structure of the Adenosine A2A Receptor in Complex with ZM241385 and the Xanthines XAC and Caffeine

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Summary

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 A2A receptor in complex with the xanthines xanthine amine congener and caffeine, as well as the A2A 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.

Highlights

► Structure of adenosine A2A receptor in ground state conformation with ionic lock ► Complete third intracellular loop present consists of extended helices 5 and 6 ► Complexes with xanthines and ZM241385 show overlapping binding interactions ► Thermostabilization enables a structure bound with the low affinity ligand caffeine

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These authors contributed equally to this work