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Mechanism of the electroneutral sodium/proton antiporter PaNhaP from transition-path shooting

Author

Listed:
  • Kei-ichi Okazaki

    (National Institutes of Natural Sciences
    Max Planck Institute of Biophysics)

  • David Wöhlert

    (Max Planck Institute of Biophysics)

  • Judith Warnau

    (Max Planck Institute of Biophysics)

  • Hendrik Jung

    (Max Planck Institute of Biophysics)

  • Özkan Yildiz

    (Max Planck Institute of Biophysics)

  • Werner Kühlbrandt

    (Max Planck Institute of Biophysics)

  • Gerhard Hummer

    (Max Planck Institute of Biophysics
    Goethe University Frankfurt)

Abstract

Na+/H+ antiporters exchange sodium ions and protons on opposite sides of lipid membranes. The electroneutral Na+/H+ antiporter NhaP from archaea Pyrococcus abyssi (PaNhaP) is a functional homolog of the human Na+/H+ exchanger NHE1, which is an important drug target. Here we resolve the Na+ and H+ transport cycle of PaNhaP by transition-path sampling. The resulting molecular dynamics trajectories of repeated ion transport events proceed without bias force, and overcome the enormous time-scale gap between seconds-scale ion exchange and microseconds simulations. The simulations reveal a hydrophobic gate to the extracellular side that opens and closes in response to the transporter domain motion. Weakening the gate by mutagenesis makes the transporter faster, suggesting that the gate balances competing demands of fidelity and efficiency. Transition-path sampling and a committor-based reaction coordinate optimization identify the essential motions and interactions that realize conformational alternation between the two access states in transporter function.

Suggested Citation

  • Kei-ichi Okazaki & David Wöhlert & Judith Warnau & Hendrik Jung & Özkan Yildiz & Werner Kühlbrandt & Gerhard Hummer, 2019. "Mechanism of the electroneutral sodium/proton antiporter PaNhaP from transition-path shooting," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09739-0
    DOI: 10.1038/s41467-019-09739-0
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    Cited by:

    1. Titouan Jaunet-Lahary & Tatsuro Shimamura & Masahiro Hayashi & Norimichi Nomura & Kouta Hirasawa & Tetsuya Shimizu & Masao Yamashita & Naotaka Tsutsumi & Yuta Suehiro & Keiichi Kojima & Yuki Sudo & Ta, 2023. "Structure and mechanism of oxalate transporter OxlT in an oxalate-degrading bacterium in the gut microbiota," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Wenxin Hu & Alex Song & Hongjin Zheng, 2024. "Substrate binding plasticity revealed by Cryo-EM structures of SLC26A2," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    3. Ashutosh Gulati & Surabhi Kokane & Annemarie Perez-Boerema & Claudia Alleva & Pascal F. Meier & Rei Matsuoka & David Drew, 2024. "Structure and mechanism of the K+/H+ exchanger KefC," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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