%0 Journal Article %A Kenneth A. Jacobson %A SIlvia Paoletta %A Vsevolod Katritch %A Beili Wu %A Zhan-Guo Gao %A Qiang Zhao %A Raymond C. Stevens %A Evgeny Kiselev %T Nucleotides Acting at P2Y Receptors: Connecting Structure and Function %D 2015 %R 10.1124/mol.114.095711 %J Molecular Pharmacology %P mol.114.095711 %X Eight G protein-coupled P2Y receptor (P2YR) subtypes are important physiological mediators. The human P2YRs are fully activated by: ATP (P2Y2, P2Y11), ADP (P2Y1, P2Y12 and P2Y13), UTP (P2Y2, P2Y4), UDP (P2Y6, P2Y14), and UDP-glucose (P2Y14). Their structural elucidation is progressing rapidly; the X-ray structures of three ligand complexes of the Gi-coupled P2Y12R and two of the Gq-coupled P2Y1R 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 P2Y1, P2Y2, P2Y4 and P2Y12Rs. Each P2YR subtype has the ability to be activated by structurally bifunctional agonists such as dinucleotides, typically dinucleoside tri- 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 homologues 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. %U https://molpharm.aspetjournals.org/content/molpharm/early/2015/04/02/mol.114.095711.full.pdf