Fig. 2.

Predicted binding mode of dapagliflozin to hSGLT1 and hSGLT2. Dapagliflozin (orange/red) adopts a similar pose to phlorizin (transparent green/red) in both hSGLT1 (a) and hSGLT2 (b). Interactions in the sugar binding site and extracellular vestibule are preserved including the electrostatic interaction with R267 (hSGLT1) and the aromatic cage formed by H80, F98, and H268 (hSGLT2). c αMDG hSGLT1 D268H (black squares) sugar currents. αMDG currents were measured at V_m = −50mV. The red dashed curve is a representative, wild-type hSGLT1 response. For the D268H mutant K_0.5 = 1.2 ± 0.1 mM, while wild-type hSGLT1 K_0.5 = 0.9 ± 0.1 mM. For c and d, data are normalized to the current measured at 10 mM αMDG. d Na⁺ dependence of αMDG currents measured in 10 mM αMDG at V_m = −50mV. For hSGLT1 D268H K_0.5 = 17 ± 1.2 mM and for wild-type hSGLT1 K_0.5 = 36 ± 1 mM. Hill coefficients hSGLT1 D268H and wild-type were 1.62 ± 0.03 and 1.61 ± 0.1. e Phlorizin and f dapagliflozin effect on the Q_max for hSGLT1 D268H, we estimated a K_i = 0.3 ± 0.1 and 0.035 ± 0.011 µM for phlorizin and dapagliflozin, respectively, while the wild-type K_i = 0.22 ± 0.04 and 0.45 ± 0.02 µM. For c–f, each data point is the mean ± SEM of n ≥ 5 oocytes