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Molecular basis of inhibition of the amino acid transporter B0AT1 (SLC6A19)

Author

Listed:
  • Junyang Xu

    (Australian National University)

  • Ziwei Hu

    (Southern University of Science and Technology)

  • Lu Dai

    (Southern University of Science and Technology)

  • Aditya Yadav

    (Australian National University)

  • Yashan Jiang

    (Australian National University)

  • Angelika Bröer

    (Australian National University)

  • Michael G. Gardiner

    (Australian National University)

  • Malcolm McLeod

    (Australian National University)

  • Renhong Yan

    (Southern University of Science and Technology)

  • Stefan Bröer

    (Australian National University)

Abstract

The epithelial neutral amino acid transporter B0AT1 (SLC6A19) is the major transporter for the absorption of neutral amino acids in the intestine and their reabsorption in the kidney. Mouse models have demonstrated that lack of B0AT1 can normalize elevated plasma amino acids in rare disorders of amino acid metabolism such as phenylketonuria and urea-cycle disorders, implying a pharmacological approach for their treatment. Here we employ a medicinal chemistry approach to generate B0AT1 inhibitors with IC50-values of 31-90 nM. High-resolution cryo-EM structures of B0AT1 in the presence of two compounds from this series identified an allosteric binding site in the vestibule of the transporter. Mechanistically, binding of these inhibitors prevents a movement of TM1 and TM6 that is required for the transporter to make a conformational change from an outward open state to the occluded state.

Suggested Citation

  • Junyang Xu & Ziwei Hu & Lu Dai & Aditya Yadav & Yashan Jiang & Angelika Bröer & Michael G. Gardiner & Malcolm McLeod & Renhong Yan & Stefan Bröer, 2024. "Molecular basis of inhibition of the amino acid transporter B0AT1 (SLC6A19)," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51748-1
    DOI: 10.1038/s41467-024-51748-1
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    References listed on IDEAS

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    1. Gregory Gauthier-Coles & Jade Vennitti & Zhiduo Zhang & William C. Comb & Shuran Xing & Kiran Javed & Angelika Bröer & Stefan Bröer, 2021. "Quantitative modelling of amino acid transport and homeostasis in mammalian cells," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    2. Per Plenge & Ara M. Abramyan & Gunnar Sørensen & Arne Mørk & Pia Weikop & Ulrik Gether & Benny Bang-Andersen & Lei Shi & Claus J. Loland, 2020. "The mechanism of a high-affinity allosteric inhibitor of the serotonin transporter," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    3. Ursula Danilczyk & Renu Sarao & Christine Remy & Chahira Benabbas & Gerti Stange & Andreas Richter & Sudha Arya & J. Andrew Pospisilik & Dustin Singer & Simone M. R. Camargo & Victoria Makrides & Tama, 2006. "Essential role for collectrin in renal amino acid transport," Nature, Nature, vol. 444(7122), pages 1088-1091, December.
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