Fig. 8. Models of the transport mechanism in Glt_Ph and LeuT.

In the outward-facing apo state (1) external gate movements (HP2 in Glt_Ph and TMs1b, 6a and EL4 in LeuT) allow for sodium binding, which stabilizes an outward-facing open state (2). This sets up a binding site for substrate and additional ion(s), leading to formation of an outward-occluded state (3). Transition to an inward-facing occluded state (4) involves piston-like motion of the transport domain (magenta and green) relative to the trimerization domain (grey) in Glt_Ph and inwardly-directed movement of EL4 and a coordinated tilt of TMs 1b,6a in LeuT. Release of the first sodium (Na2) leads to opening of the intracellular gate (HP1 in Glt_Ph and TM1a in LeuT) (5) and subsequent release of substrate and additional ion(s). In the inward-facing apo-state (6), the intracellular gate closes to allow for transition to the outward-facing apo-state.