Structural comparison of GLUT1 to GLUT3 reveal transport regulation mechanism in sugar porter family

Life Sci Alliance. 2021 Feb 3;4(4):e202000858. doi: 10.26508/lsa.202000858. Print 2021 Apr.


The human glucose transporters GLUT1 and GLUT3 have a central role in glucose uptake as canonical members of the Sugar Porter (SP) family. GLUT1 and GLUT3 share a fully conserved substrate-binding site with identical substrate coordination, but differ significantly in transport affinity in line with their physiological function. Here, we present a 2.4 Å crystal structure of GLUT1 in an inward open conformation and compare it with GLUT3 using both structural and functional data. Our work shows that interactions between a cytosolic "SP motif" and a conserved "A motif" stabilize the outward conformational state and increases substrate apparent affinity. Furthermore, we identify a previously undescribed Cl- ion site in GLUT1 and an endofacial lipid/glucose binding site which modulate GLUT kinetics. The results provide a possible explanation for the difference between GLUT1 and GLUT3 glucose affinity, imply a general model for the kinetic regulation in GLUTs and suggest a physiological function for the defining SP sequence motif in the SP family.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Biological Transport
  • Glucose / chemistry
  • Glucose / metabolism
  • Glucose Transporter Type 1 / chemistry*
  • Glucose Transporter Type 1 / genetics
  • Glucose Transporter Type 1 / metabolism*
  • Glucose Transporter Type 3 / chemistry*
  • Glucose Transporter Type 3 / genetics
  • Glucose Transporter Type 3 / metabolism*
  • Humans
  • Ligands
  • Models, Molecular*
  • Oocytes
  • Protein Binding
  • Protein Conformation*
  • Protein Interaction Domains and Motifs
  • Protein Isoforms
  • Structure-Activity Relationship
  • Sugars
  • Xenopus


  • Glucose Transporter Type 1
  • Glucose Transporter Type 3
  • Ligands
  • Protein Isoforms
  • SLC2A1 protein, human
  • SLC2A3 protein, human
  • Sugars
  • Glucose

Associated data

  • PDB/4PYP
  • PDB/4ZW9
  • PDB/5EQG
  • PDB/5EQH
  • PDB/5EQI
  • PDB/4YBQ
  • PDB/6H7D
  • PDB/4LDS
  • PDB/4YB9
  • PDB/5C65
  • PDB/4JA4
  • PDB/6THA