Two disparate ligand-binding sites in the human P2Y1 receptor

Nature. 2015 Apr 16;520(7547):317-21. doi: 10.1038/nature14287. Epub 2015 Mar 30.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate / analogs & derivatives
  • Adenosine Diphosphate / chemistry
  • Adenosine Diphosphate / metabolism
  • Binding Sites
  • Crystallography, X-Ray
  • Deoxyadenine Nucleotides / chemistry*
  • Deoxyadenine Nucleotides / metabolism*
  • Deoxyadenine Nucleotides / pharmacology
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Purinergic P2Y Receptor Antagonists / chemistry*
  • Purinergic P2Y Receptor Antagonists / metabolism
  • Purinergic P2Y Receptor Antagonists / pharmacology
  • Receptors, Purinergic P2Y1 / chemistry*
  • Receptors, Purinergic P2Y1 / metabolism*
  • Thionucleotides / chemistry
  • Thionucleotides / metabolism
  • Uracil / analogs & derivatives*
  • Uracil / chemistry
  • Uracil / metabolism
  • Uracil / pharmacology


  • 1-benzyloxymethyl-5-ethyl-6-(alpha-pyridylthio)uracil
  • 2-iodo-N(6)-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate
  • Deoxyadenine Nucleotides
  • Ligands
  • Purinergic P2Y Receptor Antagonists
  • Receptors, Purinergic P2Y1
  • Thionucleotides
  • methylthio-ADP
  • Uracil
  • Adenosine Diphosphate

Associated data

  • PDB/4XNV
  • PDB/4XNW