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

Author

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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
    Peking University)

  • 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
    Peking University)

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.

Suggested Citation

  • Yange Niu & Rui Liu & Chengcheng Guan & Yuan Zhang & Zhixing Chen & Stefan Hoerer & Herbert Nar & Lei Chen, 2022. "Structural basis of inhibition of the human SGLT2–MAP17 glucose transporter," Nature, Nature, vol. 601(7892), pages 280-284, January.
    • Handle: RePEc:nat:nature:v:601:y:2022:i:7892:d:10.1038_s41586-021-04212-9
    DOI: 10.1038/s41586-021-04212-9
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    Cited by:

    1. Farha Khan & Matthias Elgeti & Samuel Grandfield & Aviv Paz & Fiona B. Naughton & Frank V. Marcoline & Thorsten Althoff & Natalia Ermolova & Ernest M. Wright & Wayne L. Hubbell & Michael Grabe & Jeff , 2023. "Membrane potential accelerates sugar uptake by stabilizing the outward facing conformation of the Na/glucose symporter vSGLT," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Shuhui Wang & Kun Wang & Kangkang Song & Zon Weng Lai & Pengfei Li & Dongying Li & Yajie Sun & Ye Mei & Chen Xu & Maofu Liao, 2024. "Structures of the Mycobacterium tuberculosis efflux pump EfpA reveal the mechanisms of transport and inhibition," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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