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Structural insights into the mechanism of pancreatic KATP channel regulation by nucleotides

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  • Mengmeng Wang

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

  • Jing-Xiang Wu

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

  • Dian Ding

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

  • Lei Chen

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

Abstract

ATP-sensitive potassium channels (KATP) are metabolic sensors that convert the intracellular ATP/ADP ratio to the excitability of cells. They are involved in many physiological processes and implicated in several human diseases. Here we present the cryo-EM structures of the pancreatic KATP channel in both the closed state and the pre-open state, resolved in the same sample. We observe the binding of nucleotides at the inhibitory sites of the Kir6.2 channel in the closed but not in the pre-open state. Structural comparisons reveal the mechanism for ATP inhibition and Mg-ADP activation, two fundamental properties of KATP channels. Moreover, the structures also uncover the activation mechanism of diazoxide-type KATP openers.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30430-4
    DOI: 10.1038/s41467-022-30430-4
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    References listed on IDEAS

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    1. Stephen J. Tucker & Fiona M. Gribble & Chao Zhao & Stefan Trapp & Frances M. Ashcroft, 1997. "Truncation of Kir6.2 produces ATP-sensitive K+ channels in the absence of the sulphonylurea receptor," Nature, Nature, vol. 387(6629), pages 179-183, May.
    2. 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.
    3. Scott B. Hansen & Xiao Tao & Roderick MacKinnon, 2011. "Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2," Nature, Nature, vol. 477(7365), pages 495-498, September.
    4. 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. Camden M. Driggers & Yi-Ying Kuo & Phillip Zhu & Assmaa ElSheikh & Show-Ling Shyng, 2024. "Structure of an open KATP channel reveals tandem PIP2 binding sites mediating the Kir6.2 and SUR1 regulatory interface," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. 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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