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<p>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.</p>

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Substrate recognition and transport mechanism of the human proton-coupled amino-acid transporter 1 (SLC36A1)

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月7日

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  • 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

摘要

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.