Putative mechanisms for substrate transport by LeuT. (A) Classical alternating access mechanism for LeuT. Sodium ions (red spheres) and the amino acid substrate (green rhombus) bind to a central binding pocket to form a complex with the transporter. A conformational change closes external access and opens a path to the inside. After dissociation of substrates, the empty transporter undergoes a conformational change to regenerate the outward facing conformation. (B) The mechanism by Shi et al. (2008) requiring binding of two substrate molecules. This cartoon is strictly based on the model proposed by Shi et al. (2008; Fig. 7 is adapted with permission from Molecular Cell).