人质子偶联氨基酸转运体1（SLC36A1）的底物识别与转运机制
Substrate recognition and transport mechanism of the human proton-coupled amino-acid transporter 1 (SLC36A1).
摘要(中文译文)
质子偶联氨基酸转运蛋白SLC36A1（hPAT1）是一种非典型的H⁺驱动载体，介导多种两性离子氨基酸类似物的肠道吸收，包括许多具有中枢神经系统（CNS）活性的化合物，同时还参与mTORC1通路的激活以及氨基酸从溶酶体的外排，从而维持细胞氨基酸稳态。本文报道了SLC36家族成员hPAT1在无配体状态及与三种化学结构不同的底物（包括α-氨基酸D-丝氨酸、β-氨基酸哌啶酸和杂环药物D-环丝氨酸）形成复合物时的冷冻电镜结构，分辨率分别为3.4–3.5 Å。尽管这些配体的化学结构多样，但均采用空间趋同的结合模式，从而阐明了PAT1广泛底物宽泛性的结构基础。此外，我们鉴定出E270为潜在质子结合位点。上述发现共同为质子偶联氨基酸转运的分子机制提供了结构层面的见解。值得注意的是，PAT1与D-环丝氨酸结合的冷冻电镜结构展示了一种可行的口服CNS药物递送策略：利用极性骨架实现转运蛋白介导的肠道吸收和血脑屏障穿透，而无需依赖高亲脂性。
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 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.
如何引用
AMA
Jian Yin, Sensen Zhang, Chang Liu, Min Xie, Yuanzhu Gao, Maofei Chen, et al. Substrate recognition and transport mechanism of the human proton-coupled amino-acid transporter 1 (SLC36A1).. Nature communications. 2026; doi:10.1038/s41467-026-75306-z.
APA
Jian Yin, Sensen Zhang, Chang Liu, Min Xie, Yuanzhu Gao, Maofei Chen, et al (2026). Substrate recognition and transport mechanism of the human proton-coupled amino-acid transporter 1 (SLC36A1).. Nature communications. https://doi.org/10.1038/s41467-026-75306-z
GB/T 7714
Jian Yin, Sensen Zhang, Chang Liu, Min Xie, Yuanzhu Gao, Maofei Chen, et al. Substrate recognition and transport mechanism of the human proton-coupled amino-acid transporter 1 (SLC36A1).[J]. Nature communications, 2026 doi:10.1038/s41467-026-75306-z.
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