Two disparate ligand-binding sites in the human P2Y1 receptor

Dandan Zhang; Zhan-Guo Gao; Kaihua Zhang; Evgeny Kiselev; Steven Crane; Jiang Wang; Silvia Paoletta; Cuiying Yi; Limin Ma; Wenru Zhang; Gye Won Han; Hong Liu; Vadim Cherezov; Vsevolod Katritch; Hualiang Jiang; Raymond C Stevens; Kenneth A Jacobson; Qiang Zhao; Beili Wu

doi:10.1038/nature14287

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.

Authors

Dandan Zhang¹, Zhan-Guo Gao², Kaihua Zhang¹, Evgeny Kiselev², Steven Crane², Jiang Wang¹, Silvia Paoletta², Cuiying Yi¹, Limin Ma¹, Wenru Zhang¹, Gye Won Han³, Hong Liu¹, Vadim Cherezov³, Vsevolod Katritch⁴, Hualiang Jiang⁵, Raymond C Stevens⁶, Kenneth A Jacobson², Qiang Zhao¹, Beili Wu¹

Affiliations

¹ CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China.
² Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
³ Bridge Institute, Department of Chemistry, University of Southern California, Los Angeles, California 90089, USA.
⁴ Bridge Institute, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, USA.
⁵ Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China.
⁶ 1] Bridge Institute, Department of Chemistry, University of Southern California, Los Angeles, California 90089, USA [2] Bridge Institute, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, USA [3] iHuman Institute, ShanghaiTech University, 99 Haike Road, Pudong, Shanghai 201203, China.

Abstract

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding