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Structural insights into inhibitory mechanism of human excitatory amino acid transporter EAAT2

Author

Listed:
  • Takafumi Kato

    (The University of Tokyo
    The University of Oxford)

  • Tsukasa Kusakizako

    (The University of Tokyo)

  • Chunhuan Jin

    (Osaka University)

  • Xinyu Zhou

    (Osaka University)

  • Ryuichi Ohgaki

    (Osaka University
    Osaka University)

  • LiLi Quan

    (Osaka University
    National Center of Neurology and Psychiatry)

  • Minhui Xu

    (Osaka University)

  • Suguru Okuda

    (Osaka University
    The University of Tokyo)

  • Kan Kobayashi

    (The University of Tokyo
    Peptidream Inc)

  • Keitaro Yamashita

    (The University of Tokyo
    MRC Laboratory of Molecular Biology)

  • Tomohiro Nishizawa

    (The University of Tokyo
    Yokohama City University)

  • Yoshikatsu Kanai

    (Osaka University
    Osaka University)

  • Osamu Nureki

    (The University of Tokyo)

Abstract

Glutamate is a pivotal excitatory neurotransmitter in mammalian brains, but excessive glutamate causes numerous neural disorders. Almost all extracellular glutamate is retrieved by the glial transporter, Excitatory Amino Acid Transporter 2 (EAAT2), belonging to the SLC1A family. However, in some cancers, EAAT2 expression is enhanced and causes resistance to therapies by metabolic disturbance. Despite its crucial roles, the detailed structural information about EAAT2 has not been available. Here, we report cryo-EM structures of human EAAT2 in substrate-free and selective inhibitor WAY213613-bound states at 3.2 Å and 2.8 Å, respectively. EAAT2 forms a trimer, with each protomer consisting of transport and scaffold domains. Along with a glutamate-binding site, the transport domain possesses a cavity that could be disrupted during the transport cycle. WAY213613 occupies both the glutamate-binding site and cavity of EAAT2 to interfere with its alternating access, where the sensitivity is defined by the inner environment of the cavity. We provide the characterization of the molecular features of EAAT2 and its selective inhibition mechanism that may facilitate structure-based drug design for EAAT2.

Suggested Citation

  • Takafumi Kato & Tsukasa Kusakizako & Chunhuan Jin & Xinyu Zhou & Ryuichi Ohgaki & LiLi Quan & Minhui Xu & Suguru Okuda & Kan Kobayashi & Keitaro Yamashita & Tomohiro Nishizawa & Yoshikatsu Kanai & Osa, 2022. "Structural insights into inhibitory mechanism of human excitatory amino acid transporter EAAT2," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32442-6
    DOI: 10.1038/s41467-022-32442-6
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    References listed on IDEAS

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    1. Biao Qiu & Olga Boudker, 2023. "Symport and antiport mechanisms of human glutamate transporters," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
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