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 () and Beili Wu ()
Additional contact information
Dandan Zhang: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Zhan-Guo Gao: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Kaihua Zhang: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Evgeny Kiselev: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Steven Crane: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Jiang Wang: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Silvia Paoletta: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Cuiying Yi: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Limin Ma: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Wenru Zhang: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Gye Won Han: Bridge Institute, University of Southern California
Hong Liu: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Vadim Cherezov: Bridge Institute, University of Southern California
Vsevolod Katritch: Bridge Institute, University of Southern California
Hualiang Jiang: Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Raymond C. Stevens: Bridge Institute, University of Southern California
Kenneth A. Jacobson: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Qiang Zhao: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Beili Wu: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences

Nature, 2015, vol. 520, issue 7547, 317-321

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature14287

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