Structural insights into the ligand and G protein recognition by P2Y₁₃R

P2Y purinergic receptors are GPCRs that recognize extracellular nucleotides to mediate diverse physiological processes. Among 12-like subfamily members, P2Y₁₃R has well-documented roles in neuroprotection and cholesterol metabolism. Notably, P2Y₁₃R displays robust activity toward the G_q pathway in addition to its canonical G_i coupling, yet the structural basis for its ligand recognition and G protein selectivity has remained unclear. Here, we present the cryo-EM structure of the P2Y₁₃R-G_q complex bound to ADP at a resolution of 2.83 Å. The structure reveals the distinctive ligand recognition mechanism of P2Y₁₃R, in which an N-terminal arginine caps the orthosteric binding pocket. Furthermore, we also elucidated the structure of P2Y₁₄R, which shows the lowest G_i activation ability among the 12-like P2Y receptors, in complex with UDP and G_i at a resolution of 2.93 Å. Structural comparison with the 12-like P2Y receptors implicates ICL2-mediated contacts with the Gα hydrophobic cavity as a key structural determinant of G_q selectivity. Together, these findings provide mechanistic insights into nucleotide signaling and a structural foundation for advancing structure-based approaches to targeting the 12-like P2Y receptors.