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Structural identification of vasodilator binding sites on the SUR2 subunit

Author

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  • Dian Ding

    (State Key Laboratory of Membrane Biology, College of Future Technology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
    Peking-Tsinghua Center for Life Sciences, Peking University
    Academy for Advanced Interdisciplinary Studies, Peking University
    National Biomedical Imaging Center, Peking University)

  • Jing-Xiang Wu

    (State Key Laboratory of Membrane Biology, College of Future Technology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
    National Biomedical Imaging Center, Peking University)

  • Xinli Duan

    (Beijing Jingtai Technology Co., Ltd.)

  • Songling Ma

    (Beijing Jingtai Technology Co., Ltd.)

  • Lipeng Lai

    (Beijing Jingtai Technology Co., Ltd.)

  • Lei Chen

    (State Key Laboratory of Membrane Biology, College of Future Technology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
    Peking-Tsinghua Center for Life Sciences, Peking University
    Academy for Advanced Interdisciplinary Studies, Peking University
    National Biomedical Imaging Center, Peking University)

Abstract

ATP-sensitive potassium channels (KATP), composed of Kir6 and SUR subunits, convert the metabolic status of the cell into electrical signals. Pharmacological activation of SUR2- containing KATP channels by class of small molecule drugs known as KATP openers leads to hyperpolarization of excitable cells and to vasodilation. Thus, KATP openers could be used to treat cardiovascular diseases. However, where these vasodilators bind to KATP and how they activate the channel remains elusive. Here, we present cryo-EM structures of SUR2A and SUR2B subunits in complex with Mg-nucleotides and P1075 or levcromakalim, two chemically distinct KATP openers that are specific to SUR2. Both P1075 and levcromakalim bind to a common site in the transmembrane domain (TMD) of the SUR2 subunit, which is between TMD1 and TMD2 and is embraced by TM10, TM11, TM12, TM14, and TM17. These KATP openers synergize with Mg-nucleotides to stabilize SUR2 in the NBD-dimerized occluded state to activate the channel.

Suggested Citation

  • Dian Ding & Jing-Xiang Wu & Xinli Duan & Songling Ma & Lipeng Lai & Lei Chen, 2022. "Structural identification of vasodilator binding sites on the SUR2 subunit," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30428-y
    DOI: 10.1038/s41467-022-30428-y
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    References listed on IDEAS

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    1. Colin G. Nichols, 2006. "KATP channels as molecular sensors of cellular metabolism," Nature, Nature, vol. 440(7083), pages 470-476, March.
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    Cited by:

    1. Dian Ding & Tianyi Hou & Miao Wei & Jing-Xiang Wu & Lei Chen, 2023. "The inhibition mechanism of the SUR2A-containing KATP channel by a regulatory helix," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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