Structure of the human P2Y12 receptor in complex with an antithrombotic drug

P2Y receptors (P2YRs), a family of purinergic G-protein-coupled receptors (GPCRs), are activated by extracellular nucleotides. There are a total of eight distinct functional P2YRs expressed in human, which are subdivided into P2Y1-like receptors and P2Y(12)-like receptors(1). Their ligands are generally charged molecules with relatively low bioavailability and stability in vivo(2), which limits our understanding of this receptor family. P2Y(12)R regulates platelet activation and thrombus formation(3,4), and several antithrombotic drugs targeting P2Y(12)R-including the prodrugs clopidogrel (Plavix) and prasugrel (Effient) that are metabolized and bind covalently, and the nucleoside analogue ticagrelor (Brilinta) that acts directly on the receptor-have been approved for the prevention of stroke and myocardial infarction. However, limitations of these drugs (for example, a very long half-life of clopidogrel action and a characteristic adverse effect profile of ticagrelor) 5,6 suggest that there is an unfulfilled medical need for developing a new generation of P2Y(12)R inhibitors(7,8). Here we report the 2.6 angstrom resolution crystal structure of human P2Y(12)R in complex with a non-nucleotide reversible antagonist, AZD1283. The structure reveals a distinct straight conformation of helix V, which sets P2Y(12)R apart from all other known class A GPCR structures. With AZD1283 bound, the highly conserved disulphide bridge in GPCRs between helix III and extracellular loop 2 is not observed and appears to be dynamic. Along with the details of the AZD1283-binding site, analysis of the extracellular interface reveals an adjacent ligand-binding region and suggests that both pockets could be required for dinucleotide binding. The structure provides essential insights for the development of improved P2Y(12)R ligands and allosteric modulators as drug candidates.