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 and Lei Chen ()
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Yange Niu: Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
Rui Liu: Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
Chengcheng Guan: Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
Yuan Zhang: Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
Zhixing Chen: Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
Stefan Hoerer: Boehringer-Ingelheim Pharma, GmbH & Co KG
Herbert Nar: Boehringer-Ingelheim Pharma, GmbH & Co KG
Lei Chen: Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine

Nature, 2022, vol. 601, issue 7892, 280-284

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41586-021-04212-9

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