Molecular Structure of P2Y Receptors: Mutagenesis, Modeling, and Chemical Probes

There are eight subtypes of P2Y receptors (P2YRs) that are activated, and in some cases inhibited, by a range of extracellular nucleotides. These nucleotides are ubiquitous, but their extracellular concentration can rise dramatically in response to hypoxia, ischemia, or mechanical stress, injury, and release through channels and from vesicles. Two subclasses of P2YRs were defined based on clustering of sequences, second messengers, and receptor sequence analysis. The numbering system for P2YR subtypes is discontinuous; i.e., P2Y(1-14)Rs have been defined, but six of the intermediate-numbered cloned receptor sequences (e.g., P2y(3), P2y(5), P2y(7-10)) are not functional mammalian nucleotide receptors. Of these two clusters, the P2Y(12-14) subtypes couple via Gα(i) to inhibit adenylate cyclase, while the remaining subtypes couple through Gα(q) to activate phospholipase C. Collectively, the P2YRs respond to both purine and pyrimidine nucleotides, in the form of 5'-mono- and dinucleotides and nucleoside-5'-diphosphosugars. In recent years, the medicinal chemistry of P2Y receptors has advanced significantly, to provide selective agonists and antagonists for many but not all of the subtypes. Ligand design has been aided by insights from structural probing using molecular modelling and mutagenesis. Currently, the molecular modelling of the receptors is effectively based on the X-ray structure of the CXCR4 receptor, which is the closest to the P2Y receptors among all the currently crystallized receptors in terms of sequence similarity. It is now a challenge to develop novel and selective P2YR ligands for disease treatment (although antagonists of the P2Y(12)R are already widely used as antithrombotics).