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Two disparate ligand-binding sites in the human P2Y1 receptor

Author

Listed:
  • 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
    Bridge Institute, University of Southern California
    iHuman Institute, ShanghaiTech University)

  • 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)

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.

Suggested Citation

  • 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 Kat, 2015. "Two disparate ligand-binding sites in the human P2Y1 receptor," Nature, Nature, vol. 520(7547), pages 317-321, April.
  • Handle: RePEc:nat:nature:v:520:y:2015:i:7547:d:10.1038_nature14287
    DOI: 10.1038/nature14287
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    Cited by:

    1. Jae-Hyun Park & Kouki Kawakami & Naito Ishimoto & Tatsuya Ikuta & Mio Ohki & Toru Ekimoto & Mitsunori Ikeguchi & Dong-Sun Lee & Young-Ho Lee & Jeremy R. H. Tame & Asuka Inoue & Sam-Yong Park, 2023. "Structural basis for ligand recognition and signaling of hydroxy-carboxylic acid receptor 2," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Xueqian Peng & Linlin Yang & Zixuan Liu & Siyi Lou & Shiliu Mei & Meiling Li & Zhong Chen & Haitao Zhang, 2022. "Structural basis for recognition of antihistamine drug by human histamine receptor," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    3. Yang Yang & Hye Jin Kang & Ruogu Gao & Jingjing Wang & Gye Won Han & Jeffrey F. DiBerto & Lijie Wu & Jiahui Tong & Lu Qu & Yiran Wu & Ryan Pileski & Xuemei Li & Xuejun Cai Zhang & Suwen Zhao & Terry K, 2023. "Structural insights into the human niacin receptor HCA2-Gi signalling complex," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    4. Shota Suzuki & Kotaro Tanaka & Kouki Nishikawa & Hiroshi Suzuki & Atsunori Oshima & Yoshinori Fujiyoshi, 2023. "Structural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand binding," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Joshua A. Lees & João M. Dias & Francis Rajamohan & Jean-Philippe Fortin & Rebecca O’Connor & Jimmy X. Kong & Emily A. G. Hughes & Ethan L. Fisher & Jamison B. Tuttle & Gabrielle Lovett & Bethany L. K, 2023. "An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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