Structural Insights into Human Acid-sensing Ion Channel 1a Inhibition by Snake Toxin Mambalgin1

  1. Changlin Tian  Is a corresponding author
  2. Demeng Sun
  3. Sanling Liu
  4. Siyu Li
  5. Mengge Zhang
  6. Fan Yang
  7. Ming Wen
  8. Pan Shi
  9. Tao Wang
  10. Man Pan
  11. Shenghai Chang
  12. Xing Zhang
  13. Longhua Zhang
  14. Lei Liu
  1. University of Science and Tehnology of China, China
  2. University of Science and Technology of China, China
  3. Chinese Academy of Sciences, China
  4. Tsinghua University, China
  5. Zhejiang University, China

Abstract

Acid-sensing ion channels (ASICs) are proton-gated cation channels that are involved in diverse neuronal processes including pain sensing. Peptide toxin Mambalgin1 (Mamba1) from black mamba snake venom can reversibly inhibit the conductance of ASICs, showing an analgesic effect. However, the detailed inhibitory mechanism of Mamba1 on ASIC1s, especially how Mamba1 binding to extracellular domain affects the conformational changes of the transmembrane domain of ASICs remains elusive. Here, we present single-particle cryo-EM structures of human ASIC1a (hASIC1a) and hASIC1a-Mamba1 complex at resolutions of 3.56 and 3.90 Å, respectively. The structures revealed the inhibited conformation of hASIC1a upon Mamba1 binding. The combination of the structural and physiological data indicates that Mamba1 prefers to bind hASIC1a in a closed state and reduces the proton sensitivity of the channel, representing a closed-state trapping mechanism.

Data availability

The EM maps for hASIC1a and hASIC1a-Mamba1 complex have been deposited in EMDB (www.ebi.ac.uk/pdbe/emdb/) with accession codes EMD-30346 and EMD-30347. The atomic coordinates for hASIC1a and hASIC1a-Mamba1 complex have been deposited in the Protein Data Bank (www.rcsb.org) with accession codes 7CFS and 7CFT respectively

The following previously published data sets were used

Article and author information

Author details

  1. Changlin Tian

    School of Life Science, University of Science and Tehnology of China, Hefei, China
    For correspondence
    cltian@ustc.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9315-900X
  2. Demeng Sun

    School of Life Sciences, University of Science and Technology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Sanling Liu

    School of Life Science, University of Science and Tehnology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Siyu Li

    School of Life Science, University of Science and Tehnology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Mengge Zhang

    School of Life Science, University of Science and Tehnology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Fan Yang

    School of Life Science, University of Science and Tehnology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Ming Wen

    School of Life Science, University of Science and Tehnology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Pan Shi

    School of Life Science, University of Science and Tehnology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Tao Wang

    High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Man Pan

    Department of Chemistry, Tsinghua University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Shenghai Chang

    School of Medicine, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Xing Zhang

    School of Medicine, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Longhua Zhang

    School of Life Science, University of Science and Tehnology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Lei Liu

    Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.

Funding

Ministry of Science and Technology of the People's Republic of China (National Key Research and Development Project,2017YFA0505201,2017YFA0505403 and 2016YFA0400903)

  • Changlin Tian

Chinese Academy of Sciences (Queensland-Chinese Academy of Sciences (Q-CAS) Collaborative Science Fund,GJHZ201946)

  • Changlin Tian

Ministry of Science and Technology of the People's Republic of China (National Key Research and Development Project,2017YFA0505200)

  • Lei Liu

National Natural Science Foundation of China (31600601,21778051)

  • Demeng Sun

National Natural Science Foundation of China (91753205,21532004)

  • Lei Liu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Leon D Islas, Universidad Nacional Autónoma de México, Mexico

Publication history

  1. Received: March 20, 2020
  2. Accepted: September 10, 2020
  3. Accepted Manuscript published: September 11, 2020 (version 1)
  4. Version of Record published: October 13, 2020 (version 2)

Copyright

© 2020, Tian et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Changlin Tian
  2. Demeng Sun
  3. Sanling Liu
  4. Siyu Li
  5. Mengge Zhang
  6. Fan Yang
  7. Ming Wen
  8. Pan Shi
  9. Tao Wang
  10. Man Pan
  11. Shenghai Chang
  12. Xing Zhang
  13. Longhua Zhang
  14. Lei Liu
(2020)
Structural Insights into Human Acid-sensing Ion Channel 1a Inhibition by Snake Toxin Mambalgin1
eLife 9:e57096.
https://doi.org/10.7554/eLife.57096
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