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Molecular basis for inhibiting human glucose transporters by exofacial inhibitors

Author

Listed:
  • Nan Wang

    (Tsinghua University)

  • Shuo Zhang

    (Tsinghua University)

  • Yafei Yuan

    (Tsinghua University)

  • Hanwen Xu

    (Tsinghua University)

  • Elisabeth Defossa

    (Sanofi-Aventis Deutschland GmbH, R&D, Integrated Drug Discovery)

  • Hans Matter

    (Sanofi-Aventis Deutschland GmbH, R&D, Integrated Drug Discovery)

  • Melissa Besenius

    (Sanofi-Aventis Deutschland GmbH, R&D, Integrated Drug Discovery)

  • Volker Derdau

    (Sanofi-Aventis Deutschland GmbH, R&D, Integrated Drug Discovery)

  • Matthias Dreyer

    (Sanofi-Aventis Deutschland GmbH, R&D, Integrated Drug Discovery)

  • Nis Halland

    (Sanofi-Aventis Deutschland GmbH, R&D, Integrated Drug Discovery)

  • Kaihui Hu He

    (Sanofi-Aventis Deutschland GmbH, R&D, CMC Synthetics Early Development Analytics)

  • Stefan Petry

    (Sanofi-Aventis Deutschland GmbH, R&D, Integrated Drug Discovery)

  • Michael Podeschwa

    (Sanofi-Aventis Deutschland GmbH, R&D, Integrated Drug Discovery)

  • Norbert Tennagels

    (DIU Exploratory Pathobiology)

  • Xin Jiang

    (Tsinghua University
    The University of New South Wales)

  • Nieng Yan

    (Tsinghua University
    Princeton University)

Abstract

Human glucose transporters (GLUTs) are responsible for cellular uptake of hexoses. Elevated expression of GLUTs, particularly GLUT1 and GLUT3, is required to fuel the hyperproliferation of cancer cells, making GLUT inhibitors potential anticancer therapeutics. Meanwhile, GLUT inhibitor-conjugated insulin is being explored to mitigate the hypoglycemia side effect of insulin therapy in type 1 diabetes. Reasoning that exofacial inhibitors of GLUT1/3 may be favored for therapeutic applications, we report here the engineering of a GLUT3 variant, designated GLUT3exo, that can be probed for screening and validating exofacial inhibitors. We identify an exofacial GLUT3 inhibitor SA47 and elucidate its mode of action by a 2.3 Å resolution crystal structure of SA47-bound GLUT3. Our studies serve as a framework for the discovery of GLUTs exofacial inhibitors for therapeutic development.

Suggested Citation

  • Nan Wang & Shuo Zhang & Yafei Yuan & Hanwen Xu & Elisabeth Defossa & Hans Matter & Melissa Besenius & Volker Derdau & Matthias Dreyer & Nis Halland & Kaihui Hu He & Stefan Petry & Michael Podeschwa & , 2022. "Molecular basis for inhibiting human glucose transporters by exofacial inhibitors," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30326-3
    DOI: 10.1038/s41467-022-30326-3
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    References listed on IDEAS

    as
    1. Linfeng Sun & Xin Zeng & Chuangye Yan & Xiuyun Sun & Xinqi Gong & Yu Rao & Nieng Yan, 2012. "Crystal structure of a bacterial homologue of glucose transporters GLUT1–4," Nature, Nature, vol. 490(7420), pages 361-366, October.
    2. Dong Deng & Pengcheng Sun & Chuangye Yan & Meng Ke & Xin Jiang & Lei Xiong & Wenlin Ren & Kunio Hirata & Masaki Yamamoto & Shilong Fan & Nieng Yan, 2015. "Molecular basis of ligand recognition and transport by glucose transporters," Nature, Nature, vol. 526(7573), pages 391-396, October.
    3. Goragot Wisedchaisri & Min-Sun Park & Matthew G. Iadanza & Hongjin Zheng & Tamir Gonen, 2014. "Proton-coupled sugar transport in the prototypical major facilitator superfamily protein XylE," Nature Communications, Nature, vol. 5(1), pages 1-11, December.
    4. Dong Deng & Chao Xu & Pengcheng Sun & Jianping Wu & Chuangye Yan & Mingxu Hu & Nieng Yan, 2014. "Crystal structure of the human glucose transporter GLUT1," Nature, Nature, vol. 510(7503), pages 121-125, June.
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