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Cryo-EM structure of ACE2-B0AT1 complex with JX225
Structural highlights
DiseaseS6A19_HUMAN Hartnup disease;Iminoglycinuria. The disease is caused by mutations affecting the gene represented in this entry. The disease may be caused by mutations affecting the gene represented in this entry. SLC6A19 deficiency combined with haploinsufficiency of SLC6A20 or partially inactivating mutations in SLC36A2, can be responsible for hyperglycinuria. The disease may be caused by mutations affecting the gene represented in this entry. SLC6A19 deficiency combined with haploinsufficiency of SLC6A20 or partially inactivating mutations in SLC36A2, can be responsible for iminoglycinuria. Additional polymorphisms and mutations in SLC6A18 can contribute to the IG phenotype in some families. FunctionS6A19_HUMAN Transporter that mediates resorption of neutral amino acids across the apical membrane of renal and intestinal epithelial cells (PubMed:18424768, PubMed:18484095, PubMed:19185582, PubMed:26240152). This uptake is sodium-dependent and chloride-independent (PubMed:19185582, PubMed:15286788). Requires CLTRN in kidney or ACE2 in intestine for cell surface expression and amino acid transporter activity (PubMed:19185582, PubMed:18424768).[1] [2] [3] [4] [5] Publication Abstract from PubMedThe 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. Molecular basis of inhibition of the amino acid transporter B(0)AT1 (SLC6A19).,Xu J, Hu Z, Dai L, Yadav A, Jiang Y, Broer A, Gardiner MG, McLeod M, Yan R, Broer S Nat Commun. 2024 Aug 22;15(1):7224. doi: 10.1038/s41467-024-51748-1. PMID:39174516[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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