Two disparate ligand-binding sites in the human P2Y1 receptor

In response to adenosine 59-diphosphate, the P2Y(1) receptor (P2Y(1)R) facilitates platelet aggregation, and thus serves as an important antithrombotic drug target. Here we report the crystal structures of the human P2Y(1)R in complex with a nucleotide antagonist MRS2500 at 2.7 angstrom resolution, and with a non-nucleotide antagonist BPTU at 2.2 angstrom resolution. The structures reveal two distinct ligand-binding sites, providing atomic details of P2Y(1)R's unique ligand-binding modes. MRS2500 recognizes a binding site within the seven transmembrane bundle of P2Y(1)R, which is different in shape and location from the nucleotide binding site in the previously determined structure of P2Y(12)R, representative of another P2YR subfamily. BPTU binds to an allosteric pocket on the external receptor interface with the lipid bilayer, making it the first structurally characterized selective G-protein-coupled receptor (GPCR) ligand located entirely outside of the helical bundle. These high-resolutioninsights into P2Y(1)R should enable discovery of new orthosteric and allosteric antithrombotic drugs with reduced adverse effects.