Abstract
The vesicular glutamate transporters (VGLUTs) bind and move glutamate (Glu) from the cytosol into the lumen of synaptic vesicles using a H(+)-electrochemical gradient (ΔpH and Δψ) generated by the vesicular H(+)-ATPase. VGLUTs show very low Glu binding and to date, no three-dimensional structure has been elucidated. Prior studies have attempted to identify the key residues involved in binding VGLUT substrates and inhibitors using homology models and docking experiments. Recently, the inward and outward oriented crystal structures of d-galactonate transporter (DgoT) emerged as possible structure templates for VGLUT. In this review, a new homology model for VGLUT2 based on DgoT has been developed and used to conduct docking experiments to identify and differentiate residues and binding orientations involved in ligand interactions. This review describes small molecule-ligand interactions including docking using a VGLUT2 homology model derived from DgoT.