Molecular basis of inhibition of the amino acid transporter B 0 AT1 (SLC6A19).

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  • Additional Information
    • Source:
      Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
    • Publication Information:
      Original Publication: [London] : Nature Pub. Group
    • Subject Terms:
      Cryoelectron Microscopy* ; Amino Acid Transport Systems, Neutral*/metabolism ; Amino Acid Transport Systems, Neutral*/genetics ; Amino Acid Transport Systems, Neutral*/chemistry ; Amino Acid Transport Systems, Neutral*/antagonists & inhibitors; Animals ; Humans ; Mice ; Allosteric Site ; HEK293 Cells ; Binding Sites ; Protein Conformation
    • Abstract:
      The epithelial neutral amino acid transporter B 0 AT1 (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 B 0 AT1 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 B 0 AT1 inhibitors with IC 50 -values of 31-90 nM. High-resolution cryo-EM structures of B 0 AT1 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.
      (© 2024. The Author(s).)
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    • Grant Information:
      GNT2020757 Department of Health | National Health and Medical Research Council (NHMRC)
    • Accession Number:
      0 (Amino Acid Transport Systems, Neutral)
      0 (SLC6A19 protein, human)
      0 (SLC6A19 protein, mouse)
    • Publication Date:
      Date Created: 20240822 Date Completed: 20240822 Latest Revision: 20241003
    • Publication Date:
      20241003
    • Accession Number:
      PMC11341722
    • Accession Number:
      10.1038/s41467-024-51748-1
    • Accession Number:
      39174516