Structural basis of inhibition of the human SGLT2-MAP17 glucose transporter.

Yange Niu, Rui Liu, Chengcheng Guan, Yuan Zhang, Zhixing Chen, Stefan Hoerer, Herbert Nar, Lei Chen

Nature 2022 Jan

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Human sodium-glucose cotransporter 2 (hSGLT2) mediates the reabsorption of the majority of filtrated glucose in the kidney1. 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 diabetes1. 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. © 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Citation

Yange Niu, Rui Liu, Chengcheng Guan, Yuan Zhang, Zhixing Chen, Stefan Hoerer, Herbert Nar, Lei Chen. Structural basis of inhibition of the human SGLT2-MAP17 glucose transporter. Nature. 2022 Jan;601(7892):280-284