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Title | Structural basis of inhibition of the human SGLT2-MAP17 glucose transporter. |
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Journal, issue, pages | Nature, Vol. 601, Issue 7892, Page 280-284, Year 2022 |
Publish date | Dec 8, 2021 |
![]() | Yange Niu / Rui Liu / Chengcheng Guan / Yuan Zhang / Zhixing Chen / Stefan Hoerer / Herbert Nar / Lei Chen / ![]() ![]() |
PubMed Abstract | Human sodium-glucose cotransporter 2 (hSGLT2) mediates the reabsorption of the majority of filtrated glucose in the kidney. Pharmacological inhibition of hSGLT2 by oral small-molecule inhibitors, ...Human sodium-glucose cotransporter 2 (hSGLT2) mediates the reabsorption of the majority of filtrated glucose in the kidney. Pharmacological inhibition of hSGLT2 by oral small-molecule inhibitors, such as empagliflozin, leads to enhanced excretion of glucose and is widely used in the clinic to manage blood glucose levels for the treatment of type 2 diabetes. Here we determined the cryogenic electron microscopy structure of the hSGLT2-MAP17 complex in the empagliflozin-bound state to an overall resolution of 2.95 Å. Our structure shows eukaryotic SGLT-specific structural features. MAP17 interacts with transmembrane helix 13 of hSGLT2. Empagliflozin occupies both the sugar-substrate-binding site and the external vestibule to lock hSGLT2 in an outward-open conformation, thus inhibiting the transport cycle. Our work provides a framework for understanding the mechanism of SLC5A family glucose transporters and also develops a foundation for the future rational design and optimization of new inhibitors targeting these transporters. |
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Methods | EM (single particle) |
Resolution | 2.95 Å |
Structure data | EMDB-31558, PDB-7vsi: |
Chemicals | ![]() ChemComp-PLM: ![]() ChemComp-7R3: |
Source |
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![]() | TRANSPORT PROTEIN / glucose transporter / SGLT2 / SGLT |