Structural Studies Of Human Purinergic Receptor P2Y₁R

Purinergic receptor P2Y₁R, belonging to G protein-coupled receptor（GPCR） super-family, which is stimulated by adenosine diphosphate（ADP） and adenosine triphosphate（ATP）, has a broad distribution in human body. P2Y₁R plays important pathological and physiological roles in cardiovascular system, nervous system, and pancreatic island cells. Thus, P2Y₁R has been studied as an important drug target for the treatment of multiple human diseases. Structure of P2Y₁R would deepen our understanding about the biological functions of purinergic receptors, and provide structural basis and new clues for drug discovery targeting on P2Y₁R.We have been focused on structure determination of the human P2Y₁R bound to different types of ligands, including nucleotide-like antagonists, non-nucleotide antagonists, and agonists. The structures would reveal the ligand-binding landscape of P2Y₁R and provide insights into molecular mechanisms of P2Y₁R signal recognition and transduction, which will facilitate P2Y₁R drug discovery.We have determined crystal structures of P2Y₁R in complex with a nucleotide antagonist MRS2500 at 2.7 ? resolution, and with a non-nucleotide antagonist BPTU at 2.2 ? 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 P2Y₁2 R. It deepens our understanding of the diversity of signal recognition mechanisms in GPCRs. BPTU binds to an allosteric pocket on the external receptor interface with the lipid bilayer, making it the first structurally characterized selective GPCR ligand located entirely outside of the helical bundle, which opens new opportunities to broaden the scope of future GPCR ligand discovery to target novel allosteric sites outside of the canonical ligand-binding pocket. The structural studies of P2Y₁R in complex with agonists are ongoing, which will further deepen the understanding of cell signaling mechanisms of this receptor.