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

Junyang Xu, Ziwei Hu, Lu Dai, Aditya Yadav, Yashan Jiang, Angelika Bröer, Michael G. Gardiner, Malcolm McLeod, Renhong Yan () and Stefan Bröer ()
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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

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51748-1

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