“…We currently lack a complete mechanistic understanding of these properties, as some mutagenesis and comparative modeling studies support the interaction of cocaine at S1, where it could suppress transport by competing with substrate for key interactions (37,54), although other studies support binding near S2, where it could allosterically stabilize an inactive state of the transporter (94 -97). It has been proposed that these binding modes are not mutually exclusive and that cocaine may initially bind near the S2 site before transitioning to S1 following conformational changes (94,95). The current collection of LeuT and dDAT crystal structures supports multiple binding sites for substrates and inhibitors (15-19, 40, 42, 56, 60, 97, 98) and both allosteric and competitive inhibition mechanisms (6, 12, 17-20, 38, 41-43, 55, 60, 97, 99 -101).…”