9v3z
SLC36A1 bound to D-NPA
Structural highlights
FunctionS36A1_HUMAN Electrogenic proton/amino acid symporter with selectivity for small apolar L-amino acids, their D-enantiomers and selected amino acid derivatives such as 4-aminobutanoate/GABA (PubMed:12527723, PubMed:12809675, PubMed:19549785). May be involved in the efflux from the lysosomal compartment of neutral amino acids resulting from proteolysis (By similarity). May play a role in specifying sites for exocytosis in neurons (By similarity).[UniProtKB:Q924A5][1] [2] [3] Publication Abstract from PubMedThe proton-coupled amino-acid transporter SLC36A1 (hPAT1) is an atypical H(+)-driven carrier and mediates the intestinal absorption of a wide array of zwitterionic amino-acid analogs, including many compounds with central nervous-system (CNS) activity, as well as the activation of the mTORC1 pathway and the export of amino acids from lysosomes, thereby maintaining cellular amino-acid homeostasis. Here, we present the cryo-EM structures of a member of the SLC36 family, hPAT1, in its apo state and in complex with three chemically distinct substrates, including the alpha-amino acid D-serine, the beta-amino acid nipecotic acid, and the heterocyclic drug D-cycloserine, at resolutions of 3.4-3.5 A. Despite their chemical diversity, all ligands adopt a spatially convergent binding mode, elucidating the structural basis for PAT1's broad substrate promiscuity. In addition, we identify E270 as a potential proton-binding site. Together, these findings provide structural insights into the molecular mechanism of proton-coupled amino acid transport. Notably, the cryo-EM structure of PAT1 bound to D-cycloserine illustrates a viable oral CNS drug delivery strategy: exploiting polar scaffolds to achieve transporter-mediated intestinal absorption and blood-brain barrier penetration without relying on high lipophilicity. Substrate recognition and transport mechanism of the human proton-coupled amino-acid transporter 1 (SLC36A1).,Yin J, Zhang S, Liu C, Xie M, Gao Y, Chen M, Wang Y, Chen M, Fan H, Yang Z, Li H, Liang L, Zhou B, Chen X, Yang M Nat Commun. 2026 Jul 7. doi: 10.1038/s41467-026-75306-z. PMID:42414312[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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