Structure and mechanism of the SGLT family of glucose transporters

Lei Han, Qianhui Qu, Deniz Aydin, Ouliana Panova, Michael J. Robertson, Yan Xu, Ron O. Dror, Georgios Skiniotis () and Liang Feng ()
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Lei Han: Stanford University School of Medicine
Qianhui Qu: Stanford University School of Medicine
Ouliana Panova: Stanford University School of Medicine
Michael J. Robertson: Stanford University School of Medicine
Yan Xu: Stanford University School of Medicine
Ron O. Dror: Stanford University School of Medicine
Georgios Skiniotis: Stanford University School of Medicine
Liang Feng: Stanford University School of Medicine

Nature, 2022, vol. 601, issue 7892, 274-279

Abstract: Abstract Glucose is a primary energy source in living cells. The discovery in 1960s that a sodium gradient powers the active uptake of glucose in the intestine1 heralded the concept of a secondary active transporter that can catalyse the movement of a substrate against an electrochemical gradient by harnessing energy from another coupled substrate. Subsequently, coupled Na+/glucose transport was found to be mediated by sodium–glucose cotransporters2,3 (SGLTs). SGLTs are responsible for active glucose and galactose absorption in the intestine and for glucose reabsorption in the kidney4, and are targeted by multiple drugs to treat diabetes5. Several members within the SGLT family transport key metabolites other than glucose2. Here we report cryo-electron microscopy structures of the prototypic human SGLT1 and a related monocarboxylate transporter SMCT1 from the same family. The structures, together with molecular dynamics simulations and functional studies, define the architecture of SGLTs, uncover the mechanism of substrate binding and selectivity, and shed light on water permeability of SGLT1. These results provide insights into the multifaceted functions of SGLTs.

Date: 2022
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DOI: 10.1038/s41586-021-04211-w

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