2. Academic Validation
  3. Structural basis of inhibition of the human SGLT2-MAP17 glucose transporter

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

  • Nature. 2022 Jan;601(7892):280-284. doi: 10.1038/s41586-021-04212-9.
Yange Niu 1,  Rui Liu 1,  Chengcheng Guan 1,  Yuan Zhang 1,  Zhixing Chen 1 2,  Stefan Hoerer 3,  Herbert Nar 3,  Lei Chen 4 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Membrane Biology, College of Future Technology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Beijing, China.
  • 2 Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
  • 3 Boehringer-Ingelheim Pharma, GmbH & Co KG, Biberach, Germany.
  • 4 State Key Laboratory of Membrane Biology, College of Future Technology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Beijing, China. chenlei2016@pku.edu.cn.
  • 5 Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China. chenlei2016@pku.edu.cn.
PMID: 34880493 DOI: 10.1038/s41586-021-04212-9
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.

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