Structure of “Caffeine Receptor” Solved

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A2A structureCollaborating scientists at the Scripps Research Institute and The Amsterdam Center for Drug Research have determined the crystal structure of the human adenosine A2A receptor, also known as the caffeine receptor. The receptor is a member of the hetero-trimeric G-protein coupled receptor (GPCR) superfamily and plays an important role in mediating responses to adenosine in many physiological processes. The scientists were able to obtain crystals of the protein by binding it to a potent adenosine antagonist, ZM241385, which had been developed as a potential drug to combat Parkinson’s disease. Full details have been published in the journal Science.

Despite the importance of GPCRs as drug targets, determination of their crystallographic structure has proven difficult. This new structure follows the success of the Scripps team’s publication of the β2-adrenergic receptor structure last year.

Adenosine interacts with a number of GPCRs including the A1, A2A, A2B, and A3 subtypes. Each of these plays a role in responding to adenosine in the central nervous system in pain regulation, cerebral blood flow, basal ganglia functions, respiration, and sleep. Insights obtained from the study of the A2A structure have already suggested mechanisms for receptor subtype selectivity.

It is hoped that this new information will help in the design of new drugs that could be important in the treatment of numerous neurological disorders, including Parkinson’s and Huntington disease.

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