Cryo-EM structure of the human adenosine A_2B receptor-G_s signaling complex

The human adenosine A_2B receptor (A_2BR) is a class A G protein-coupled receptor that is involved in several major physiological and pathological processes throughout the body. A_2BR recognizes its ligands adenosine and NECA with relatively low affinity, but the detailed mechanism for its ligand recognition and signaling is still elusive. Here, we present two structures determined by cryo-electron microscopy of A_2BR bound to its agonists NECA and BAY60-6583, each coupled to an engineered G_s protein. The structures reveal conserved orthosteric binding pockets with subtle differences, whereas the selectivity or specificity can mainly be attributed to regions extended from the orthosteric pocket. We also found that BAY60-6583 occupies a secondary pocket, where residues V250^6.51 and N273^7.36 were two key determinants for its selectivity against A_2BR. This study offers a better understanding of ligand selectivity for the adenosine receptor family and provides a structural template for further development of A_2BR ligands for related diseases.