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Ligand binding and conformational changes of SUR1 subunit in pancreatic ATP-sensitive potassium channels

Jing-Xiang Wu, Dian Ding, Mengmeng Wang, Yunlu Kang, Xin Zeng, Lei Chen
doi: https://doi.org/10.1101/283440
Jing-Xiang Wu
1State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Beijing 100871, China
2Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
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Dian Ding
1State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Beijing 100871, China
2Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
3Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
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Mengmeng Wang
1State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Beijing 100871, China
2Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
3Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
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Yunlu Kang
1State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Beijing 100871, China
2Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
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Xin Zeng
1State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Beijing 100871, China
2Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
3Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
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Lei Chen
1State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Beijing 100871, China
2Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
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  • For correspondence: chenlei2016@pku.edu.cn
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ABSTRACT

ATP-sensitive potassium channels (KATP) are energy sensors on the plasma membrane. By sensing the intracellular ADP/ATP ratio of β-cells, pancreatic KATP channels control insulin release and regulate metabolism at the whole body level. They are implicated in many metabolic disorders and diseases and are therefore important drug targets. Here, we present three structures of pancreatic KATP channels solved by cryo-electron microscopy (cryo-EM), at resolutions ranging from 4.1 to 4.5 Å. These structures depict the binding site of the antidiabetic drug glibenclamide, indicate how Kir6.2 N-terminus participates the coupling between the peripheral SUR1 subunit and the central Kir6.2 channel, reveal the binding mode of activating nucleotides, and suggest the mechanism of how Mg-ADP binding on nucleotide binding domains (NBDs) drives a conformational change of the SUR1 subunit.

  • ABBREVIATIONS

    KATP
    ATP-sensitive potassium channel
    cryo-EM
    cryo-electron microscopy
    SUR
    sulfonylurea receptor
    Kir6
    inward-rectifying potassium channel 6
    GBM
    glibenclamide
    ABC
    ATP-binding cassettes
    TMD0-L0
    transmembrane domain 0-loop 0
    NBD
    nucleotide binding domain
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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    Posted March 16, 2018.
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    Ligand binding and conformational changes of SUR1 subunit in pancreatic ATP-sensitive potassium channels
    Jing-Xiang Wu, Dian Ding, Mengmeng Wang, Yunlu Kang, Xin Zeng, Lei Chen
    bioRxiv 283440; doi: https://doi.org/10.1101/283440
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    Ligand binding and conformational changes of SUR1 subunit in pancreatic ATP-sensitive potassium channels
    Jing-Xiang Wu, Dian Ding, Mengmeng Wang, Yunlu Kang, Xin Zeng, Lei Chen
    bioRxiv 283440; doi: https://doi.org/10.1101/283440

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