Abstract
Sodium-Galactose Transporter (SGLT) is a secondary active symporter able to accumulate sugars like glucose/galactose into cells using the electrochemical gradient of Na+ across the membrane. This transport is believed to occur via an alternating-access mechanism in which the protein, switching from an outward to an inward-conformation, guarantees a correct uptake of sugar molecules important in intestinal absorption and renal reabsorption. The protein belongs to the five-helix inverted repeat (5HIR) superfamily of sodium-dependent cotransporters where, despite the low sequence identity, it has been observed a common structural core of 10 transmembrane helices.In 2008 Faham et al solved the crystal structure of SGLT of the Vibrio parahaemolyticus bacterium (vSGLT), where the Na+ ion was not detected. The protein was so classified as representing an ‘ion-releasing’ state (Li et al, Biophys J, 2009). Moreover, the precise mechanism of the binding/unbinding of Na+ and galactose from the inward-facing conformation and the gating role of Y263 were not clear. In this study, using classical molecular dynamics (MD) simulations and bias-exchange metadynamics, we identified a candidate ion-retaining state of the transporter (Bisha et al, J Chem Theor Comput, 2013). Furthermore, we found that the interplay between the two ligands is based on a weakly coupled mechanism in which the role of Y263 seems to be not relevant for the exiting of the galactose towards the cytoplasm.
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