Cryo-EM structures of adenosine receptor A 3 AR bound to selective agonists.

The adenosine A ₃ receptor (A ₃ AR), a key member of the G protein-coupled receptor family, is a promising therapeutic target for inflammatory and cancerous conditions. The selective A ₃ AR agonists, CF101 and CF102, are clinically significant, yet their recognition mechanisms remained elusive. Here we report the cryogenic electron microscopy structures of the full-length human A ₃ AR bound to CF101 and CF102 with heterotrimeric G _i protein in complex at 3.3-3.2 Å resolution. These agonists reside in the orthosteric pocket, forming conserved interactions via their adenine moieties, while their 3-iodobenzyl groups exhibit distinct orientations. Functional assays reveal the critical role of extracellular loop 3 in A ₃ AR's ligand selectivity and receptor activation. Key mutations, including His ^3.37 , Ser ^5.42 , and Ser ^6.52 , in a unique sub-pocket of A ₃ AR, significantly impact receptor activation. Comparative analysis with the inactive A _2A AR structure highlights a conserved receptor activation mechanism. Our findings provide comprehensive insights into the molecular recognition and signaling of A ₃ AR, paving the way for designing subtype-selective adenosine receptor ligands.
(© 2024. The Author(s).)