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Structural basis of organic cation transporter-3 inhibition

Author

Listed:
  • Basavraj Khanppnavar

    (Laboratory of Biomolecular Research, Paul Scherrer Institute
    Institute of Molecular Biology and Biophysics, ETH Zurich)

  • Julian Maier

    (Medical University of Vienna)

  • Freja Herborg

    (University of Copenhagen)

  • Ralph Gradisch

    (Medical University of Vienna)

  • Erika Lazzarin

    (Medical University of Vienna)

  • Dino Luethi

    (Medical University of Vienna)

  • Jae-Won Yang

    (Medical University of Vienna)

  • Chao Qi

    (Laboratory of Biomolecular Research, Paul Scherrer Institute)

  • Marion Holy

    (Medical University of Vienna)

  • Kathrin Jäntsch

    (Medical University of Vienna)

  • Oliver Kudlacek

    (Medical University of Vienna)

  • Klaus Schicker

    (Medical University of Vienna)

  • Thomas Werge

    (Institute of Biological Psychiatry, Mental Health Services Copenhagen
    University of Copenhagen
    The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH)
    University of Copenhagen)

  • Ulrik Gether

    (University of Copenhagen)

  • Thomas Stockner

    (Medical University of Vienna)

  • Volodymyr M. Korkhov

    (Laboratory of Biomolecular Research, Paul Scherrer Institute
    Institute of Molecular Biology and Biophysics, ETH Zurich)

  • Harald H. Sitte

    (Medical University of Vienna)

Abstract

Organic cation transporters (OCTs) facilitate the translocation of catecholamines, drugs and xenobiotics across the plasma membrane in various tissues throughout the human body. OCT3 plays a key role in low-affinity, high-capacity uptake of monoamines in most tissues including heart, brain and liver. Its deregulation plays a role in diseases. Despite its importance, the structural basis of OCT3 function and its inhibition has remained enigmatic. Here we describe the cryo-EM structure of human OCT3 at 3.2 Å resolution. Structures of OCT3 bound to two inhibitors, corticosterone and decynium-22, define the ligand binding pocket and reveal common features of major facilitator transporter inhibitors. In addition, we relate the functional characteristics of an extensive collection of previously uncharacterized human genetic variants to structural features, thereby providing a basis for understanding the impact of OCT3 polymorphisms.

Suggested Citation

  • Basavraj Khanppnavar & Julian Maier & Freja Herborg & Ralph Gradisch & Erika Lazzarin & Dino Luethi & Jae-Won Yang & Chao Qi & Marion Holy & Kathrin Jäntsch & Oliver Kudlacek & Klaus Schicker & Thomas, 2022. "Structural basis of organic cation transporter-3 inhibition," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34284-8
    DOI: 10.1038/s41467-022-34284-8
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    References listed on IDEAS

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    Cited by:

    1. Yi C. Zeng & Meghna Sobti & Ada Quinn & Nicola J. Smith & Simon H. J. Brown & Jamie I. Vandenberg & Renae M. Ryan & Megan L. O’Mara & Alastair G. Stewart, 2023. "Structural basis of promiscuous substrate transport by Organic Cation Transporter 1," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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