Molecular basis of metal transport by human ZnT10.

Manganese is essential for immunity and neurological health, and its dysregulation causes Parkinsonism and dystonia. We present cryo-electron microscopy (cryo-EM) structures of human ZnT10, a Mn2+/Zn2+ transporter, in symmetric inward-facing and asymmetric inward/outward states. Conformational shifts in TM1, TM2, TM4, and TM5, along with rearranged protomer interactions, control substrate access. Structural analysis reveals the substrate-binding sites for Mn2+ and endogenous Zn2+ in ZnT10. Molecular dynamic simulation also provides supportive evidence for the ion coordination. Mn2+ transitions between distinct coordination sites during conformational changes, whereas Zn2+ remains bound in the same pocket. Radial distribution functions (RDF) indicate that Zn2+ requires more water coordination, making it a less preferred substrate. These results clarify the molecular basis of metal recognition and selectivity in ZnT10, providing key insights into manganese specificity determinants.