Fig. 1.

Kinetic scheme for SGLT substrate and ion transport. (A) Each number represents a conformation (state) that the carrier occupies in sequence during the transport cycle. Influx experiments suggest an ordered binding scheme for substrate (pink) and sodium (yellow) at the extracellular face, but the order of events for the inward-facing state are less clear. The standard six-state model in which substrate unbinds before Na⁺ was developed previously and nicely fits existing data. However, previous simulations on the bacterial transporter vSGLT suggest that Na⁺ may unbind first. Here, we highlight a third possibility, skipping state 5, in which substrate and ion binding are independent and occur in a random order. vSGLT carries out transport with one ion, whereas hSGLT1 uses two. The arrows indicate the direction corresponding to inward pumping; however, SGLT is fully reversible, as exploited in this study. (B) Structure of SGLT in the inward-facing conformation bound to Na⁺ and sugar (state 4). The structure is of vSGLT (PDB ID code 3DH4), which does not contain an Na1 Na⁺ binding site. The approximate position of the Na1 site in hSGLT1 is marked with a yellow circle based on functional data (13).