Nucleotides Acting at P2Y Receptors: Connecting Structure and Function

Eight G protein-coupled P2Y receptor (P2YR) subtypes are important physiologic mediators. The human P2YRs are fully activated by ATP (P2Y(2) and P2Y(11)), ADP (P2Y(1), P2Y(12), and P2Y(13)), UTP (P2Y(2) and P2Y(4)), UDP (P2Y(6) and P2Y(14)), and UDP glucose (P2Y(14)). Their structural elucidation is progressing rapidly. The X-ray structures of three ligand complexes of the G(i)-coupled P2Y(12)R and two of the G(q)-coupled P2Y(1)Rs were recently determined and will be especially useful in structure-based ligand design at two P2YR subfamilies. These high-resolution structures, which display unusual binding site features, complement mutagenesis studies for probing ligand recognition and activation. The structural requirements for nucleotide agonist recognition at P2YRs are relatively permissive with respect to the length of the phosphate moiety, but less so with respect to base recognition. Nucleotide-like antagonists and partial agonists are also known for P2Y(1), P2Y(2), P2Y(4), and P2Y(12)Rs. Each P2YR subtype has the ability to be activated by structurally bifunctional agonists, such as dinucleotides, typically, dinucleoside triphosphates or tetraphosphates, and nucleoside polyphosphate sugars (e.g., UDP glucose) as well as the more conventional mononucleotide agonists. A range of dinucleoside polyphosphates, from triphosphates to higher homologs, occurs naturally. Earlier modeling predictions of the P2YRs were not very accurate, but recent findings have provided much detailed structural insight into this receptor family to aid in the rational design of new drugs.