Structural Basis of the Selective Sugar Transport in Sodium-Glucose Cotransporters

J Mol Biol. 2022 Mar 15;434(5):167464. doi: 10.1016/j.jmb.2022.167464. Epub 2022 Jan 22.


Sodium-glucose cotransporters (SGLTs) are responsible for sugar absorption in small intestine and renal tubule epithelial cells. These proteins have attracted clinical attention as a cause of malabsorption and as a target for diabetes drugs. Each SGLT isoform has strict selectivity for its monosaccharide substrate. Few studies have attempted to elucidate the structural basis of sugar selectivity by allowing generating SGLT mutants that bind substrates not normally transported or by reproducing the substrate specificity of other isoforms. In this study, we built a structural homology model for the substrate binding states of human SGLT1 (hSGLT1), which primarily transports glucose and galactose. We also performed electrophysiological analysis of hSGLT1 using various natural sugars and mutants. By mutating the K321 residue, which forms hydrophilic interactions in the sugar binding pocket, we induced mannose and allose transport. We also changed the glucose/galactose transport ratio, which reproduces the substrate specificity of the prokaryotic galactose transporter. By adding mutations one-by-one to the residues in the binding pocket, we were able to reproduce the substrate specificity of SGLT4, which transports fructose. This suggests that fructose, which exhibits various structures in equilibrium, binds to SGLT in a pyranose conformation. These results reveal one state of the structural basis that determines selective transport by SGLT. These findings will be useful for predicting the substrates of other glucose transporters and to design effective inhibitors.

Keywords: SGLT; ion transport; membrane transporter; structure–function relationship; substrate recognition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Transport
  • Fructose / metabolism
  • Galactose / metabolism
  • Glucose / metabolism
  • Humans
  • Models, Molecular
  • Mutation
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism
  • Sodium-Glucose Transporter 1* / chemistry
  • Sodium-Glucose Transporter 1* / genetics
  • Sodium-Glucose Transporter 1* / metabolism
  • Substrate Specificity


  • Protein Isoforms
  • SLC5A1 protein, human
  • Sodium-Glucose Transporter 1
  • Fructose
  • Glucose
  • Galactose