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Inhibitor binding mode and allosteric regulation of Na+-glucose symporters

Author

Listed:
  • Paola Bisignano

    (University of California
    University of California)

  • Chiara Ghezzi

    (David Geffen School of Medicine at UCLA)

  • Hyunil Jo

    (University of California
    University of California)

  • Nicholas F. Polizzi

    (University of California
    University of California)

  • Thorsten Althoff

    (David Geffen School of Medicine at UCLA)

  • Chakrapani Kalyanaraman

    (University of California)

  • Rosmarie Friemann

    (Centre for Antibiotic Resistance (CARe) at University of Gothenburg)

  • Matthew P. Jacobson

    (University of California)

  • Ernest M. Wright

    (David Geffen School of Medicine at UCLA)

  • Michael Grabe

    (University of California
    University of California)

Abstract

Sodium-dependent glucose transporters (SGLTs) exploit sodium gradients to transport sugars across the plasma membrane. Due to their role in renal sugar reabsorption, SGLTs are targets for the treatment of type 2 diabetes. Current therapeutics are phlorizin derivatives that contain a sugar moiety bound to an aromatic aglycon tail. Here, we develop structural models of human SGLT1/2 in complex with inhibitors by combining computational and functional studies. Inhibitors bind with the sugar moiety in the sugar pocket and the aglycon tail in the extracellular vestibule. The binding poses corroborate mutagenesis studies and suggest a partial closure of the outer gate upon binding. The models also reveal a putative Na+ binding site in hSGLT1 whose disruption reduces the transport stoichiometry to the value observed in hSGLT2 and increases inhibition by aglycon tails. Our work demonstrates that subtype selectivity arises from Na+-regulated outer gate closure and a variable region in extracellular loop EL5.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07700-1
    DOI: 10.1038/s41467-018-07700-1
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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. 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.
    3. 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.
    4. August George & Paola Bisignano & John M Rosenberg & Michael Grabe & Daniel M Zuckerman, 2020. "A systems-biology approach to molecular machines: Exploration of alternative transporter mechanisms," PLOS Computational Biology, Public Library of Science, vol. 16(7), pages 1-21, July.

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