Structure and mechanism of the mammalian fructose transporter GLUT5

Nature. 2015 Oct 15;526(7573):397-401. doi: 10.1038/nature14909. Epub 2015 Sep 30.

Abstract

The altered activity of the fructose transporter GLUT5, an isoform of the facilitated-diffusion glucose transporter family, has been linked to disorders such as type 2 diabetes and obesity. GLUT5 is also overexpressed in certain tumour cells, and inhibitors are potential drugs for these conditions. Here we describe the crystal structures of GLUT5 from Rattus norvegicus and Bos taurus in open outward- and open inward-facing conformations, respectively. GLUT5 has a major facilitator superfamily fold like other homologous monosaccharide transporters. On the basis of a comparison of the inward-facing structures of GLUT5 and human GLUT1, a ubiquitous glucose transporter, we show that a single point mutation is enough to switch the substrate-binding preference of GLUT5 from fructose to glucose. A comparison of the substrate-free structures of GLUT5 with occluded substrate-bound structures of Escherichia coli XylE suggests that, in addition to global rocker-switch-like re-orientation of the bundles, local asymmetric rearrangements of carboxy-terminal transmembrane bundle helices TM7 and TM10 underlie a 'gated-pore' transport mechanism in such monosaccharide transporters.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Biological Transport
  • Cattle
  • Cell Membrane / metabolism
  • Crystallography, X-Ray
  • Escherichia coli / chemistry
  • Escherichia coli Proteins / chemistry
  • Escherichia coli Proteins / metabolism
  • Fructose / chemistry
  • Fructose / metabolism*
  • Glucose / chemistry
  • Glucose / metabolism
  • Glucose Transporter Type 1 / chemistry
  • Glucose Transporter Type 1 / metabolism
  • Glucose Transporter Type 5 / chemistry*
  • Glucose Transporter Type 5 / genetics
  • Glucose Transporter Type 5 / metabolism*
  • Models, Molecular
  • Point Mutation / genetics
  • Protein Conformation
  • Rats
  • Salts / chemistry
  • Static Electricity
  • Structure-Activity Relationship
  • Substrate Specificity / genetics
  • Symporters / chemistry
  • Symporters / metabolism

Substances

  • Escherichia coli Proteins
  • Glucose Transporter Type 1
  • Glucose Transporter Type 5
  • SLC2A1 protein, human
  • Salts
  • Slc2a5 protein, rat
  • Symporters
  • xylE protein, E coli
  • Fructose
  • Glucose

Associated data

  • PDB/4YB9
  • PDB/4YBQ