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- W4317761823 abstract "Abstract Selective sodium-glucose cotransporter 2 (SGLT2) plays an important role in glucose reabsorption. SGLT2 inhibitors suppress glucose reabsorption from the kidneys, thus reducing blood glucose levels in type 2 diabetes patients. We and other groups have developed several SGLT2 inhibitors starting from a natural product, phlorizin, but their action mechanisms remain unknown. Here, we elucidated the physiological hSGLT2–MAP17 complex structures bound to five SGLT2 inhibitors using single-particle cryo-electron microscopy. Canagliflozin, dapagliflozin, TA-1887, and sotagliflozin were bound in the outward-facing structure, whereas phlorizin was bound in the inward-open structure. The phlorizin–hSGLT2 interaction biochemically exhibited biphasic binding. Phlorizin weakly binds, via the phloretin motif, from its intracellular side near the Na + -binding site, while strongly interacts from its extracellular side. Unexpectedly, bound Na + stabilizes the outward-open conformation, while its release allows the transporter to adopt inward-open state. Our results first visualized the Na + -binding and inward-open conformation of hSGLT2–MAP17, clarifying the unprecedented Na + -dependent sugar transport mechanism with MAP17 acting as a scaffold, and may pave the way for development of next-generation SGLT inhibitors." @default.
- W4317761823 created "2023-01-23" @default.
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- W4317761823 date "2023-01-23" @default.
- W4317761823 modified "2023-10-01" @default.
- W4317761823 title "Structural insights into the mechanism of the human SGLT2–MAP17 glucose transporter" @default.
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- W4317761823 doi "https://doi.org/10.1101/2023.01.23.524988" @default.
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