Figure 7: Inward-to-outward return transition of the NSS family.
From: A conserved leucine occupies the empty substrate site of LeuT in the Na+-free return state
In the inward-open state, LeuT gets protonated on Glu290 (ref. 15), and Leu25 (red spheres) presumably moves into the substrate-binding pocket (white arrow) (1). From an occluded inward-oriented return state LeuT can switch to the occluded outward-oriented state described here (2). TM1b is flexible and this state is likely prone to H+ release (dashed line) and Leu25 relocation out of the substrate-binding pocket (white arrow) allowing Na+ ions to bind (3). Na+ binding at the Na1 and Na2 sites stabilize the outward-open state and the transporter is ready for substrate binding and the forward transport cycle.
