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
  • 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. [email protected].
  • 5. Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China. [email protected].
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.