2. Academic Validation
  3. Molecular basis of inhibition of the amino acid transporter B0AT1 (SLC6A19)

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

  • Nat Commun. 2024 Aug 22;15(1):7224. doi: 10.1038/s41467-024-51748-1.
Junyang Xu # 1,  Ziwei Hu # 2,  Lu Dai # 2,  Aditya Yadav # 3,  Yashan Jiang # 3,  Angelika Bröer 3,  Michael G Gardiner 1,  Malcolm McLeod 1,  Renhong Yan 4,  Stefan Bröer 5
Affiliations

Affiliations

  • 1 Research School of Chemistry, Australian National University, Canberra, ACT, Australia.
  • 2 Department of Biochemistry, Key University Laboratory of Metabolism and Health of Guangdong, School of Medicine, Institute for Biological Electron Microscopy, Southern University of Science and Technology, Shenzhen, Guangdong, China.
  • 3 Research School of Biology, Australian National University, Canberra, ACT, Australia.
  • 4 Department of Biochemistry, Key University Laboratory of Metabolism and Health of Guangdong, School of Medicine, Institute for Biological Electron Microscopy, Southern University of Science and Technology, Shenzhen, Guangdong, China. yanrh@sustech.edu.cn.
  • 5 Research School of Biology, Australian National University, Canberra, ACT, Australia. stefan.broeer@anu.edu.au.
  • # Contributed equally.
PMID: 39174516 DOI: 10.1038/s41467-024-51748-1
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.

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