Sodium-glucose cotransporters are responsible for the accumulation of glucose and galactose in cells ranging from bacteria to man. They belong to a large gene family, the SGLT gene family, where a common function appears to be sodium (or proton) cotransport of substrates such as sugars, ions, amino acids and vitamins. We have previously proposed a cotransport model where ion-substrate cotransport occurs by ligand- and voltage-induced conformation changes, and where the rate and direction of transport is a function of voltage and the concentration of the ligands on each side of the membrane. Our recent studies to test this model have focused on the structure and function of two family members, the human and Vibrio paraheamolyticus Na⁺-glucose and galactose cotransporters, hSGLT1 and vSGLT. Both proteins have been expressed in E. coli and Xenopus laevis oocytes for functional studies and both have been purified to homogeneity from E. coli and reconstituted into liposomes for structural studies using electron microscopic and spectroscopic methods (Turk et al. 2000; Quick & Wright, 2002). Oocytes were harvested from frogs anaesthetized with Tricaine in accordance with UCLA and NIH animal welfare guidelines. In this presentation I will summarize our data showing ligand-induced global changes in conformation of vSGLT in proteoliposomes using attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy and H/D exchange (Le Coutre et al. 2002), and ligand- and voltage-induced local changes in conformation in proteoliposomes and oocytes using extrinsic fluorescence probes covalently attached to designated cysteine mutants (Meinild et al. 2002). Freeze fracture electron microscopy demonstrated that both the functional cotransporters are monomers. ATR-FTIR reveals stepwise increases in helical content of vSGLT upon binding of sodium and D-galactose, and this is accompanied by stepwise reductions in H/D exchange. These experiments indicate discrete conformational changes in the protein during the catalytic transport cycle of the protein. Fluorescence studies of both vSGLT and hSGLT1 show that the conformational changes involve specific domain in helices 10, 11 and 12 and the extracellular linker between helices 10 and 11. These results support our kinetic model for transport and they are incorporated into a structural model.