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Structural mechanism of SGLT1 inhibitors

Author

Listed:
  • Yange Niu

    (Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
    Peking University)

  • Wenhao Cui

    (Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
    Peking University
    Shandong University)

  • Rui Liu

    (Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
    Peking University)

  • Sanshan Wang

    (Peking University
    Synthetic and Functional Biomolecules Center)

  • Han Ke

    (Peking University
    Synthetic and Functional Biomolecules Center)

  • Xiaoguang Lei

    (Peking University
    Synthetic and Functional Biomolecules Center)

  • Lei Chen

    (Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
    Peking University
    Peking University)

Abstract

Sodium glucose co-transporters (SGLT) harness the electrochemical gradient of sodium to drive the uphill transport of glucose across the plasma membrane. Human SGLT1 (hSGLT1) plays a key role in sugar uptake from food and its inhibitors show promise in the treatment of several diseases. However, the inhibition mechanism for hSGLT1 remains elusive. Here, we present the cryo-EM structure of the hSGLT1-MAP17 hetero-dimeric complex in the presence of the high-affinity inhibitor LX2761. LX2761 locks the transporter in an outward-open conformation by wedging inside the substrate-binding site and the extracellular vestibule of hSGLT1. LX2761 blocks the putative water permeation pathway of hSGLT1. The structure also uncovers the conformational changes of hSGLT1 during transitions from outward-open to inward-open states.

Suggested Citation

  • Yange Niu & Wenhao Cui & Rui Liu & Sanshan Wang & Han Ke & Xiaoguang Lei & Lei Chen, 2022. "Structural mechanism of SGLT1 inhibitors," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33421-7
    DOI: 10.1038/s41467-022-33421-7
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    References listed on IDEAS

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    1. Weixiao Y. Wahlgren & Elin Dunevall & Rachel A. North & Aviv Paz & Mariafrancesca Scalise & Paola Bisignano & Johan Bengtsson-Palme & Parveen Goyal & Elin Claesson & Rhawnie Caing-Carlsson & Rebecka A, 2018. "Substrate-bound outward-open structure of a Na+-coupled sialic acid symporter reveals a new Na+ site," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    2. Chengcheng Guan & Yange Niu & Si-Cong Chen & Yunlu Kang & Jing-Xiang Wu & Koji Nishi & Catherine C. Y. Chang & Ta-Yuan Chang & Tuoping Luo & Lei Chen, 2020. "Structural insights into the inhibition mechanism of human sterol O-acyltransferase 1 by a competitive inhibitor," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    3. Paola Bisignano & Chiara Ghezzi & Hyunil Jo & Nicholas F. Polizzi & Thorsten Althoff & Chakrapani Kalyanaraman & Rosmarie Friemann & Matthew P. Jacobson & Ernest M. Wright & Michael Grabe, 2018. "Inhibitor binding mode and allosteric regulation of Na+-glucose symporters," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
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    Cited by:

    1. Wenhao Cui & Yange Niu & Zejian Sun & Rui Liu & Lei Chen, 2023. "Structures of human SGLT in the occluded state reveal conformational changes during sugar transport," Nature Communications, Nature, vol. 14(1), pages 1-10, December.

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