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Cryo-EM structures of ClC-2 chloride channel reveal the blocking mechanism of its specific inhibitor AK-42

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  • Tao Ma

    (Chinese Academy of Sciences
    Southern University of Science and Technology)

  • Lei Wang

    (Southern University of Science and Technology)

  • Anping Chai

    (Chinese Academy of Sciences
    Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions)

  • Chao Liu

    (Southern University of Science and Technology)

  • Wenqiang Cui

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Shuguang Yuan

    (Chinese Academy of Sciences)

  • Shannon Wing Ngor Au

    (The Chinese University of Hong Kong)

  • Liang Sun

    (Shenzhen Shuli Tech Co., Ltd)

  • Xiaokang Zhang

    (Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions
    Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Zhenzhen Zhang

    (Southern University of Science and Technology)

  • Jianping Lu

    (Shenzhen Mental Health Center)

  • Yuanzhu Gao

    (Southern University of Science and Technology)

  • Peiyi Wang

    (Southern University of Science and Technology)

  • Zhifang Li

    (Southern University of Science and Technology)

  • Yujie Liang

    (Shenzhen Mental Health Center)

  • Horst Vogel

    (Chinese Academy of Sciences
    Ecole Polytechnique Fédérale de Lausanne (EPFL))

  • Yu Tian Wang

    (Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Daping Wang

    (Southern University of Science and Technology
    The First Affiliated Hospital of Shenzhen University)

  • Kaige Yan

    (Southern University of Science and Technology)

  • Huawei Zhang

    (Chinese Academy of Sciences
    Southern University of Science and Technology)

Abstract

ClC-2 transports chloride ions across plasma membranes and plays critical roles in cellular homeostasis. Its dysfunction is involved in diseases including leukodystrophy and primary aldosteronism. AK-42 was recently reported as a specific inhibitor of ClC-2. However, experimental structures are still missing to decipher its inhibition mechanism. Here, we present cryo-EM structures of apo ClC-2 and its complex with AK-42, both at 3.5 Å resolution. Residues S162, E205 and Y553 are involved in chloride binding and contribute to the ion selectivity. The side-chain of the gating glutamate E205 occupies the putative central chloride-binding site, indicating that our structure represents a closed state. Structural analysis, molecular dynamics and electrophysiological recordings identify key residues to interact with AK-42. Several AK-42 interacting residues are present in ClC-2 but not in other ClCs, providing a possible explanation for AK-42 specificity. Taken together, our results experimentally reveal the potential inhibition mechanism of ClC-2 inhibitor AK-42.

Suggested Citation

  • Tao Ma & Lei Wang & Anping Chai & Chao Liu & Wenqiang Cui & Shuguang Yuan & Shannon Wing Ngor Au & Liang Sun & Xiaokang Zhang & Zhenzhen Zhang & Jianping Lu & Yuanzhu Gao & Peiyi Wang & Zhifang Li & Y, 2023. "Cryo-EM structures of ClC-2 chloride channel reveal the blocking mechanism of its specific inhibitor AK-42," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39218-6
    DOI: 10.1038/s41467-023-39218-6
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