Fig. 5.

Allosteric model of inhibitor binding to SGLTs. The binding of phlorizin-like inhibitors to the outward-facing state of SGLTs leads to a partial closure of the TM9-10 outer gate in an induced fit mechanism. a, c Binding of 2 Na⁺ to hSGLT1 stabilizes the outer gate in an open conformation making it less favorable for the gate to close over the aglycon tails of inhibitors. b, d The absence of the Na3 site in hSGLT2 makes partial closure and inhibitor binding more favorable and therefore the inhibitors more potent. Additionally, elements of EL5_C (red) contribute to better binding to hSGLT2