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Crystal structures of the gastric proton pump

Author

Listed:
  • Kazuhiro Abe

    (Nagoya University
    Nagoya University
    Japan Science and Technology Corporation)

  • Katsumasa Irie

    (Nagoya University
    Nagoya University)

  • Hanayo Nakanishi

    (Nagoya University
    Japan Science and Technology Corporation)

  • Hiroshi Suzuki

    (The Rockefeller University)

  • Yoshinori Fujiyoshi

    (Nagoya University
    Japan Science and Technology Corporation
    CeSPIA Inc.)

Abstract

The gastric proton pump—the H+, K+-ATPase—is a P-type ATPase responsible for acidifying the gastric juice down to pH 1. This corresponds to a million-fold proton gradient across the membrane of the parietal cell, the steepest known cation gradient of any mammalian tissue. The H+, K+-ATPase is an important target for drugs that treat gastric acid-related diseases. Here we present crystal structures of the H+, K+-ATPase in complex with two blockers, vonoprazan and SCH28080, in the luminal-open state, at 2.8 Å resolution. The drugs have partially overlapping but clearly distinct binding modes in the middle of a conduit running from the gastric lumen to the cation-binding site. The crystal structures suggest that the tight configuration at the cation-binding site lowers the pK a value of Glu820 sufficiently to enable the release of a proton even into the pH 1 environment of the stomach.

Suggested Citation

  • Kazuhiro Abe & Katsumasa Irie & Hanayo Nakanishi & Hiroshi Suzuki & Yoshinori Fujiyoshi, 2018. "Crystal structures of the gastric proton pump," Nature, Nature, vol. 556(7700), pages 214-218, April.
    • Handle: RePEc:nat:nature:v:556:y:2018:i:7700:d:10.1038_s41586-018-0003-8
    DOI: 10.1038/s41586-018-0003-8
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    Citations

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    Cited by:

    1. Takuto Fujii & Shushi Nagamori & Pattama Wiriyasermkul & Shizhou Zheng & Asaka Yago & Takahiro Shimizu & Yoshiaki Tabuchi & Tomoyuki Okumura & Tsutomu Fujii & Hiroshi Takeshima & Hideki Sakai, 2023. "Parkinson’s disease-associated ATP13A2/PARK9 functions as a lysosomal H+,K+-ATPase," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    2. Victoria C. Young & Hanayo Nakanishi & Dylan J. Meyer & Tomohiro Nishizawa & Atsunori Oshima & Pablo Artigas & Kazuhiro Abe, 2022. "Structure and function of H+/K+ pump mutants reveal Na+/K+ pump mechanisms," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Phong T. Nguyen & Christine Deisl & Michael Fine & Trevor S. Tippetts & Emiko Uchikawa & Xiao-chen Bai & Beth Levine, 2022. "Structural basis for gating mechanism of the human sodium-potassium pump," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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