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

Autor: Xu J; Research School of Chemistry, Australian National University, Canberra, ACT, Australia., Hu Z; 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., Dai L; 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., Yadav A; Research School of Biology, Australian National University, Canberra, ACT, Australia., Jiang Y; Research School of Biology, Australian National University, Canberra, ACT, Australia., Bröer A; Research School of Biology, Australian National University, Canberra, ACT, Australia., Gardiner MG; Research School of Chemistry, Australian National University, Canberra, ACT, Australia., McLeod M; Research School of Chemistry, Australian National University, Canberra, ACT, Australia., Yan R; 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., Bröer S; Research School of Biology, Australian National University, Canberra, ACT, Australia. stefan.broeer@anu.edu.au.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 22; Vol. 15 (1), pp. 7224. Date of Electronic Publication: 2024 Aug 22.
DOI: 10.1038/s41467-024-51748-1
Abstrakt: 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).)
Databáze: MEDLINE
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