Abstract
Taurine is a sulfur-containing amino acid that plays several crucial roles in the body. Its uptake is mediated by the taurine transporter (TauT). Genetic mutations and dysregulation of TauT have been linked to various neurological disorders, cardiomyopathy, childhood progressive retinal degeneration, and cancer, making TauT a promising target for therapeutic intervention in these diseases. However, the structure and mechanism of TauT remain poorly understood. In this study, we present the structures of the human taurine transporter (hTauT) under four conditions: the substrate-free state, the taurine-bound state, the β-alanine-bound state, and the cyclic inhibitor piperidine-4-sulfonate (P4S)-bound state. These structures reveal that taurine binds at the central substrate-binding site of hTauT. Notably, β-alanine and the cyclic P4S inhibitors also mimic taurine, occupying the same substrate-binding site. In the substrate-free and P4S-bound forms, hTauT also adopt an inward-open conformation, where transmembrane helix TM1a bends toward the membrane, facilitating the opening of the intracellular gate for ion and substrate release. These structural insights enhance our understanding of the mechanisms underlying substrate and ion recognition and transport in hTauT, paving the way for the future development of taurine transporter substrate analogues or selective inhibitors.
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Data availability
Cryo-EM maps of hTauT generated in this study have been deposited in the Electron Microscopy Data Bank under the accession codes: EMD-62738 (the inward-open conformation of the substrate-free state), EMD-62739 (the inward-occluded conformation of the substrate-free state), EMD-62740 (the taurine-bound state), EMD-62741 (the β-alanine-bound state), EMD-62742 (the inward-open conformation of the P4S-bound state), and EMD-62743 (the inward-occluded conformation of the P4S-bound state), respectively. Atomic models of hTauT generated in this study have been deposited in the Protein Data Bank under the accession codes: 9L19 (the inward-open conformation of the substrate-free state), 9L1A (the inward-occluded conformation of the substrate-free state), 9L1B (the taurine-bound state), 9L1C (the β-alanine-bound state), 9L1D (the inward-open conformation of the P4S-bound state), and 9L1E (the inward-occluded conformation of the P4S-bound state), respectively. The entries used in this study are available in the Protein Data Bank under accession code: 9EO4, 7Y7W, 4US3, 7Y7V, 9CP5, 9J8B, 3TT3, 8HFF, 8WFI, 8ZPB, and 8WFL. Source data are provided with this paper.
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Acknowledgements
We thank all of Wu Lab’s members for their kind help. The authors appreciate the AKTA purification platform provided by labs of Pingping Li and Bing Cui, and the centrifuge experimental platform provided by the Biological Analysis Center at Institute of Materia Medica of Chinese Academy of Medical Sciences. Our work was supported by the Electron Microscopy Laboratory, and Cryo-EM Platform of Peking University, and we would be grateful to Xuemei Li, Zhenxi Guo, Changdong Qin, Xiaojuan Hui, and Guopeng Wang for their help in making EM samples and taking/analyzing EM images. We also thank Shuimu BioSciences for Cryo-EM facility access and technical support during image acquisition. The work is supported by grants from the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (no. 2022-RC350-01 to J.-X.W.), the CAMS Innovation Fund for Medical Sciences (CIFMS) (2023-I2M-2-006 to J.-X.W. and 2021-I2M-3-001 to R.W.), and the National Natural Science Foundation of China (32522046 and 32371266 to J.-X.W.).
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J.-X.W. initiated the project. Y.Q., Y. Zhang, D.W., and X.C. screened the expression constructs. Y.Q. and Y. Zhang purified protein, prepared the cryo-EM sample, and screened the cryo-EM sample. Y.Q., Y. Zhang, and W. J. collected the cryo-EM data. Y.Q. and J.-X.W. processed the cryo-EM data. Y.Q., Y. Zhou, and J.-X.W. built and refined the atomic model. Y.Q., Y. Zhang, D.W., and J.L. performed the uptake assay. L.L. and R.W. contributed to chemicals. All authors contributed to the manuscript preparation.
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Qi, Y., Zhang, Y., Wang, D. et al. Structural mechanism of substrate binding and inhibition of human taurine transporter. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70772-x
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DOI: https://doi.org/10.1038/s41467-026-70772-x
