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| Title | Substrate recognition and transport mechanism of the human proton-coupled amino-acid transporter 1 (SLC36A1). |
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| Journal, issue, pages | Nat Commun, Year 2026 |
| Publish date | Jul 7, 2026 |
 Authors | Jian Yin / Sensen Zhang / Chang Liu / Min Xie / Yuanzhu Gao / Maofei Chen / Yixue Wang / Meiying Chen / Hongxuan Fan / Zi Yang / Huan Li / Li Liang / Boda Zhou / Xudong Chen / Maojun Yang /  |
| PubMed Abstract | The 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 ...The 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 α-amino acid D-serine, the β-amino acid nipecotic acid, and the heterocyclic drug D-cycloserine, at resolutions of 3.4-3.5 Å. 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. |
 External links | Nat Commun / PubMed:42414312 |
| Methods | EM (single particle) |
| Resolution | 3.37 - 3.73 Å |
| Structure data | EMDB-64756, PDB-9v3t: EMDB-64757, PDB-9v3v: EMDB-64759, PDB-9v3x: EMDB-64762, PDB-9v3z: |
| Chemicals |  ChemComp-NAG:  ChemComp-4AX:  ChemComp-DSN:  PDB-1bdb: |
| Source |
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 Keywords | TRANSPORT PROTEIN / lysosomal membrane protein apo / lysosomal membrane protein D-ser / lysosomal membrane protein ser / lysosomal membrane protein NPA |
homo sapiens (human)