Conformational changes of TRPML1 between the PI(3,5)P2-bound closed and PI(3,5)P2/Tem-bound open states. (A) Structural comparison of TRPML1 between the PI(3,5)P2-bound closed (magenta) and PI(3,5)P2/Tem-bound open (green) states. (B) Conformational changes at the Tem-binding region. Arrows indicate the Tem-induced movements at S5 and S4 from the neighboring subunit (labeled as S4′). (C) Two subtle movements at the PI(3,5)P2-binding region. Arrows indicate the movements from the closed to open state. (D) Zoomed-in view of the R403/Y404-mediated bending movement of S4. (E) Zoomed-in view of R403/Y404-mediated interactions that are observed in the open state (Right) but absent in the closed state (Left). (F) Top view of the pore-opening movement induced by the outward movement of the S4 C terminus. (G) Top view of the counterclockwise rotation of the luminal linker domain from the closed to open state.