In response to adenosine 5′-diphosphate, the P2Y1 receptor (P2Y1R) facilitates platelet aggregation, and thus serves as an important antithrombotic drug target. Here we report the crystal structures of the human P2Y1R in complex with a nucleotide antagonist MRS2500 at 2.7 Å resolution, and with a non-nucleotide antagonist BPTU at 2.2 Å resolution. The structures reveal two distinct ligand-binding sites, providing atomic details of P2Y1R's unique ligand-binding modes. MRS2500 recognizes a binding site within the seven transmembrane bundle of P2Y1R, which is different in shape and location from the nucleotide binding site in the previously determined structure of P2Y12R, 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-resolution insights into P2Y1R should enable discovery of new orthosteric and allosteric antithrombotic drugs with reduced adverse effects. Two X-ray crystal structures are presented of the human P2Y1 G-protein-coupled receptor, which is an important target for anti-thrombotic drugs; the structures unexpectedly reveal two ligand-binding sites. In this manuscript, Beili Wu and colleagues report X-ray crystal structures of the human P2Y1 receptor, a G-protein-coupled receptor (GPCR). Like the P2Y12 receptor, this membrane protein regulates platelet activation and thrombus formation. Both GPCRs are important targets for the development of new antithrombotic drugs. Comparison of this structure to a previously published P2Y12 receptor structure indicates that the orthosteric ligand-binding sites of these two GPRCs are quite different: the binding site of the P2Y1 receptor is much shallower than the binding site of the P2Y12 receptor. The authors solved structures of the protein in the presence of the nucleotide antagonist MRS2500 and the non-nucleotide antagonist BPTU. MRS2500 binds in the orthosteric site, but BPTU binds to an unusual pocket at the GPCR/lipid bilayer interface.

Two disparate ligand-binding sites in the human P2Y1 receptor