Structural mechanism of substrate binding and inhibition of human taurine transporter

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. Taurine transporter TauT is a key drug target for multiple diseases. Here, authors reveal structure of human TauT in four states, showing how inhibitors mimic taurine and guiding future TauT-targeted drug design.