Structure of the human taurine transporter TauT reveals substrate recognition and mechanisms of inhibition

Taurine, a sulfur-containing amino acid, plays a crucial role in human health due to its antioxidant, anti-inflammatory, osmoregulatory properties ^1,2 . Taurine levels are primarily regulated by the sodium-/chloride-dependent taurine transporter (TauT) ³ . Inhibitors of TauT have potential in the treatment of certain diseases, including neurological disorders and cancer ^4,5 . Here, we present five structures of TauT: in the substrate-free apo state, in complex with taurine and in complex with taurine-mimetic inhibitors β-alanine, GABA and guanidinoethyl sulfonate (GES), each with varying length of linear structure, in both inward-facing and occluded conformations. The taurine-, β-alanine- and GABA-bound hTauT structures, in the presence of NaCl, adopt an occluded conformation, with ligands binding in the central pocket. In the presence of KCl, GES-bound hTauT adopts an inward-facing conformation, with two molecules positioned along the substrate translocation pathway with one into the deep central cavity and the other precluded conformational change from inward-facing to occluded state. Combined with function analysis, our structures provided insights into the overall architecture, substrate coordination and inhibitor recognition mechanisms of TauT.