Structural determination of the human taurine transporter TauT reveals the mechanism of substrate and inhibitor recognition

Taurine, a sulfur-containing amino acid, is vital for human health because of its antioxidant, anti-inflammatory, and osmoregulatory properties. Its homeostasis is maintained by the Na⁺/Cl^--dependent taurine transporter (TauT). Here, we present five atomic structures of human TauT: apo, taurine bound, and complexes with three taurine-mimetic inhibitors, including β-alanine, γ-aminobutyric acid (GABA), and guanidinoethyl sulfonate (GES). The structures of taurine-, β-alanine-, and GABA-bound human TauT (hTauT) in complex with NaCl adopt an occluded conformation, with ligands binding in a central pocket. With KCl, GES-bound hTauT adopts an inward-facing conformation, with two GES positioned along the substrate translocation pathway in a bipartite manner: one in the deep central cavity and the other precluding structural transition to the occluded state. The radioactive taurine uptake analyses clearly demonstrate the impact of residues on taurine recognition and inhibitor selection. These structures provide insights into the overall architecture, substrate coordination, and inhibitor recognition mechanism of TauT.