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Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors

Author

Listed:
  • Anastasiia Gusach

    (Moscow Institute of Physics and Technology)

  • Aleksandra Luginina

    (Moscow Institute of Physics and Technology)

  • Egor Marin

    (Moscow Institute of Physics and Technology)

  • Rebecca L. Brouillette

    (Université de Sherbrooke)

  • Élie Besserer-Offroy

    (Université de Sherbrooke)

  • Jean-Michel Longpré

    (Université de Sherbrooke)

  • Andrii Ishchenko

    (University of Southern California
    University of Southern California
    Merck & Co Inc.)

  • Petr Popov

    (Moscow Institute of Physics and Technology
    Skolkovo Institute of Science and Technology)

  • Nilkanth Patel

    (University of Southern California
    University of Southern California)

  • Taku Fujimoto

    (Ono Pharmaceutical Co., Ltd.)

  • Toru Maruyama

    (Ono Pharmaceutical Co., Ltd.)

  • Benjamin Stauch

    (University of Southern California
    University of Southern California)

  • Margarita Ergasheva

    (Moscow Institute of Physics and Technology)

  • Daria Romanovskaia

    (Moscow Institute of Physics and Technology
    CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Anastasiia Stepko

    (Moscow Institute of Physics and Technology)

  • Kirill Kovalev

    (Moscow Institute of Physics and Technology
    Research Center Jülich
    Université Grenoble Alpes–Commissariat à l’Energie Atomique et aux Energies Alternatives–CNRS
    Research Center Jülich)

  • Mikhail Shevtsov

    (Moscow Institute of Physics and Technology)

  • Valentin Gordeliy

    (Moscow Institute of Physics and Technology
    Research Center Jülich
    Université Grenoble Alpes–Commissariat à l’Energie Atomique et aux Energies Alternatives–CNRS
    Research Center Jülich)

  • Gye Won Han

    (University of Southern California
    University of Southern California)

  • Vsevolod Katritch

    (University of Southern California
    University of Southern California
    University of Southern California)

  • Valentin Borshchevskiy

    (Moscow Institute of Physics and Technology
    Research Center Jülich
    Research Center Jülich)

  • Philippe Sarret

    (Université de Sherbrooke)

  • Alexey Mishin

    (Moscow Institute of Physics and Technology)

  • Vadim Cherezov

    (Moscow Institute of Physics and Technology
    University of Southern California
    University of Southern California
    University of Southern California)

Abstract

Cysteinyl leukotriene G protein-coupled receptors CysLT1 and CysLT2 regulate pro-inflammatory responses associated with allergic disorders. While selective inhibition of CysLT1R has been used for treating asthma and associated diseases for over two decades, CysLT2R has recently started to emerge as a potential drug target against atopic asthma, brain injury and central nervous system disorders, as well as several types of cancer. Here, we describe four crystal structures of CysLT2R in complex with three dual CysLT1R/CysLT2R antagonists. The reported structures together with the results of comprehensive mutagenesis and computer modeling studies shed light on molecular determinants of CysLTR ligand selectivity and specific effects of disease-related single nucleotide variants.

Suggested Citation

  • Anastasiia Gusach & Aleksandra Luginina & Egor Marin & Rebecca L. Brouillette & Élie Besserer-Offroy & Jean-Michel Longpré & Andrii Ishchenko & Petr Popov & Nilkanth Patel & Taku Fujimoto & Toru Maruy, 2019. "Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13348-2
    DOI: 10.1038/s41467-019-13348-2
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    Cited by:

    1. Na Wang & Xinheng He & Jing Zhao & Hualiang Jiang & Xi Cheng & Yu Xia & H. Eric Xu & Yuanzheng He, 2022. "Structural basis of leukotriene B4 receptor 1 activation," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. 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.

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