biostudies-literatureShen XFudan UniversityChina Postdoctoral Science FoundationMinistry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology)National Natural Science Foundation of China (National Science Foundation of China)8581https://www.ebi.ac.uk/biostudies/studies/S-EPMC12480533biostudies-literatureUnknown16(1)Manganese ion (Mn²⁺) is crucial for various physiological processes, yet excessive levels disrupt cellular homeostasis and impair the function of multiple organelles. The transporter SLC30A10 plays a pivotal role in Mn²⁺ homeostasis by exporting Mn²⁺ from cells, preventing toxic effects. Mutations in the SLC30A10 gene result in Mn²⁺ accumulation and lead to disorders such as hypermanganesemia with dystonia 1 (HMNDYT1). Despite its physiological significance, the structural basis underlying Mn²⁺ binding and the detailed transport mechanisms of SLC30A10 remain unknown. Here, we present diverse conformations of high-resolution cryo-electron microscopy (cryo-EM) structures that reveal a Mn²⁺-binding site in SLC30A10, setting it apart from other SLC30 family transporters. Furthermore, we show tNature communicationsMolecular mechanisms of SLC30A10-mediated manganese transport.PMC1248053332171216STI2030-Major Projects 2022ZD02126002023M73068923216Zhang JKYang HSun PWang SGuo XZhong HShen XHe RfalseMolecular mechanisms of SLC30A10-mediated manganese transport.Manganese ion (Mn²⁺) is crucial for various physiological processes, yet excessive levels disrupt cellular homeostasis and impair the function of multiple organelles. The transporter SLC30A10 plays a pivotal role in Mn²⁺ homeostasis by exporting Mn²⁺ from cells, preventing toxic effects. Mutations in the SLC30A10 gene result in Mn²⁺ accumulation and lead to disorders such as hypermanganesemia with dystonia 1 (HMNDYT1). Despite its physiological significance, the structural basis underlying Mn²⁺ binding and the detailed transport mechanisms of SLC30A10 remain unknown. Here, we present diverse conformations of high-resolution cryo-electron microscopy (cryo-EM) structures that reveal a Mn²⁺-binding site in SLC30A10, setting it apart from other SLC30 family transporters. Furthermore, we show t2025-01-01T00:00:00Z2025 Sep2026-06-04T00:00:45.274Z2026-05-03T03:12:08.394ZS-EPMC124805334102272010.1038/s41467-025-63616-7