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Two disparate ligand-binding sites in the human P2Y1 receptor. 2015

Dandan Zhang, and Zhan-Guo Gao, and Kaihua Zhang, and Evgeny Kiselev, and Steven Crane, and Jiang Wang, and Silvia Paoletta, and Cuiying Yi, and Limin Ma, and Wenru Zhang, and Gye Won Han, and Hong Liu, and Vadim Cherezov, and Vsevolod Katritch, and Hualiang Jiang, and Raymond C Stevens, and Kenneth A Jacobson, and Qiang Zhao, and Beili Wu
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China.

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.

UI MeSH Term Description Entries
D008024 Ligands A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed) Ligand
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D008968 Molecular Conformation The characteristic three-dimensional shape of a molecule. Molecular Configuration,3D Molecular Structure,Configuration, Molecular,Molecular Structure, Three Dimensional,Three Dimensional Molecular Structure,3D Molecular Structures,Configurations, Molecular,Conformation, Molecular,Conformations, Molecular,Molecular Configurations,Molecular Conformations,Molecular Structure, 3D,Molecular Structures, 3D,Structure, 3D Molecular,Structures, 3D Molecular
D003838 Deoxyadenine Nucleotides Adenine nucleotides which contain deoxyribose as the sugar moiety. Deoxyadenosine Phosphates,Nucleotides, Deoxyadenine,Phosphates, Deoxyadenosine
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000244 Adenosine Diphosphate Adenosine 5'-(trihydrogen diphosphate). An adenine nucleotide containing two phosphate groups esterified to the sugar moiety at the 5'-position. ADP,Adenosine Pyrophosphate,Magnesium ADP,MgADP,Adenosine 5'-Pyrophosphate,5'-Pyrophosphate, Adenosine,ADP, Magnesium,Adenosine 5' Pyrophosphate,Diphosphate, Adenosine,Pyrophosphate, Adenosine
D001665 Binding Sites The parts of a macromolecule that directly participate in its specific combination with another molecule. Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining
D013873 Thionucleotides Nucleotides in which the base moiety is substituted with one or more sulfur atoms.
D014498 Uracil One of four nucleotide bases in the nucleic acid RNA.
D058472 Receptors, Purinergic P2Y1 A subclass of purinergic P2Y receptors that have a preference for ATP and ADP. The activated P2Y1 receptor signals through the G-PROTEIN-coupled activation of PHOSPHOLIPASE C and mobilization of intracellular CALCIUM. P2Y1 Purinoceptor,P2Y1 Purinoceptors,P2Y1 Receptor,P2Y1 Receptors,Purinergic Receptor P2Y, G-Protein Coupled, 1,Purinoceptor P2Y1,P2Y1 Receptors, Purinergic,Purinergic P2Y1 Receptors,Purinoceptor, P2Y1,Purinoceptors, P2Y1,Receptor, P2Y1,Receptors, P2Y1

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