Crystal structure of the adenosine A 2A receptor bound to an antagonist reveals a potential allosteric pocket

Significance The A 2A R is a G protein-coupled receptor (GPCR) that plays important roles in cardiovascular physiology and immune function. The A 2A R is also a target for the treatment of Parkinson’s disease, where A 2A R antagonists have been shown to enhance signaling through the D2 dopamine receptor. Here we present the crystal structure of the A 2A R bound to a novel bitopic antagonist. As a result of structural changes needed to accommodate the bound antagonist, crystals could not be grown in lipidic cubic phase. Instead, crystals were grown in detergent with a type II packing rarely observed in GPCR crystals. The structure revealed a potential allosteric pocket that that can be exploited to develop subtype-selective allosteric modulators.