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The inhibition mechanism of the SUR2A-containing KATP channel by a regulatory helix

Author

Listed:
  • Dian Ding

    (Beijing Key Laboratory of Cardiometabolic Molecular Medicine
    Peking University
    Peking University
    Peking University)

  • Tianyi Hou

    (Beijing Key Laboratory of Cardiometabolic Molecular Medicine
    Peking University
    Peking University
    Peking University)

  • Miao Wei

    (Beijing Key Laboratory of Cardiometabolic Molecular Medicine
    Peking University)

  • Jing-Xiang Wu

    (Beijing Key Laboratory of Cardiometabolic Molecular Medicine
    Peking University)

  • Lei Chen

    (Beijing Key Laboratory of Cardiometabolic Molecular Medicine
    Peking University
    Peking University)

Abstract

KATP channels are metabolic sensors for intracellular ATP/ADP ratios, play essential roles in many physiological processes, and are implicated in a spectrum of pathological conditions. SUR2A-containing KATP channels differ from other subtypes in their sensitivity to Mg-ADP activation. However, the underlying structural mechanism remains poorly understood. Here we present a series of cryo-EM structures of SUR2A in the presence of different combinations of Mg-nucleotides and the allosteric inhibitor repaglinide. These structures uncover regulatory helix (R helix) on the NBD1-TMD2 linker, which wedges between NBD1 and NBD2. R helix stabilizes SUR2A in the NBD-separated conformation to inhibit channel activation. The competitive binding of Mg-ADP with Mg-ATP to NBD2 mobilizes the R helix to relieve such inhibition, allowing channel activation. The structures of SUR2B in similar conditions suggest that the C-terminal 42 residues of SUR2B enhance the structural dynamics of NBD2 and facilitate the dissociation of the R helix and the binding of Mg-ADP to NBD2, promoting NBD dimerization and subsequent channel activation.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39379-4
    DOI: 10.1038/s41467-023-39379-4
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    References listed on IDEAS

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    1. Nitesh Kumar Khandelwal & Cinthia R. Millan & Samantha I. Zangari & Samantha Avila & Dewight Williams & Tarjani M. Thaker & Thomas M. Tomasiak, 2022. "The structural basis for regulation of the glutathione transporter Ycf1 by regulatory domain phosphorylation," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Mengmeng Wang & Jing-Xiang Wu & Dian Ding & Lei Chen, 2022. "Structural insights into the mechanism of pancreatic KATP channel regulation by nucleotides," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    3. 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.
    4. Marie F. Smeland & Conor McClenaghan & Helen I. Roessler & Sanne Savelberg & Geir Åsmund Myge Hansen & Helene Hjellnes & Kjell Arne Arntzen & Kai Ivar Müller & Andreas Rosenberger Dybesland & Theresa , 2019. "ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9," Nature Communications, Nature, vol. 10(1), pages 1-19, December.
    5. 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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