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

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 bou...

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Autores principales: Bisignano, Paola, Ghezzi, Chiara, Jo, Hyunil, Polizzi, Nicholas F., Althoff, Thorsten, Kalyanaraman, Chakrapani, Friemann, Rosmarie, Jacobson, Matthew P., Wright, Ernest M., Grabe, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286348/
https://www.ncbi.nlm.nih.gov/pubmed/30532032
http://dx.doi.org/10.1038/s41467-018-07700-1
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author Bisignano, Paola
Ghezzi, Chiara
Jo, Hyunil
Polizzi, Nicholas F.
Althoff, Thorsten
Kalyanaraman, Chakrapani
Friemann, Rosmarie
Jacobson, Matthew P.
Wright, Ernest M.
Grabe, Michael
author_facet Bisignano, Paola
Ghezzi, Chiara
Jo, Hyunil
Polizzi, Nicholas F.
Althoff, Thorsten
Kalyanaraman, Chakrapani
Friemann, Rosmarie
Jacobson, Matthew P.
Wright, Ernest M.
Grabe, Michael
author_sort Bisignano, Paola
collection PubMed
description 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.
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spelling pubmed-62863482018-12-11 Inhibitor binding mode and allosteric regulation of Na(+)-glucose symporters Bisignano, Paola Ghezzi, Chiara Jo, Hyunil Polizzi, Nicholas F. Althoff, Thorsten Kalyanaraman, Chakrapani Friemann, Rosmarie Jacobson, Matthew P. Wright, Ernest M. Grabe, Michael Nat Commun Article 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. Nature Publishing Group UK 2018-12-07 /pmc/articles/PMC6286348/ /pubmed/30532032 http://dx.doi.org/10.1038/s41467-018-07700-1 Text en © The Author(s 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Bisignano, Paola
Ghezzi, Chiara
Jo, Hyunil
Polizzi, Nicholas F.
Althoff, Thorsten
Kalyanaraman, Chakrapani
Friemann, Rosmarie
Jacobson, Matthew P.
Wright, Ernest M.
Grabe, Michael
Inhibitor binding mode and allosteric regulation of Na(+)-glucose symporters
title Inhibitor binding mode and allosteric regulation of Na(+)-glucose symporters
title_full Inhibitor binding mode and allosteric regulation of Na(+)-glucose symporters
title_fullStr Inhibitor binding mode and allosteric regulation of Na(+)-glucose symporters
title_full_unstemmed Inhibitor binding mode and allosteric regulation of Na(+)-glucose symporters
title_short Inhibitor binding mode and allosteric regulation of Na(+)-glucose symporters
title_sort inhibitor binding mode and allosteric regulation of na(+)-glucose symporters
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286348/
https://www.ncbi.nlm.nih.gov/pubmed/30532032
http://dx.doi.org/10.1038/s41467-018-07700-1
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