Structural and comparative analysis of GLUT1 and GLUT3 and transport regulation in the Sugar Porter family

The human glucose transporters GLUT1 and GLUT3 are canonical members of the Sugar Porter (SP) family and central for uptake of glucose. GLUT1 and GLUT3 share a fully conserved substratebinding site with identical substrate coordination, but differ significantly in transport affinity in accordance with their physiological function. Here we present a 2.4 Å crystal structure of GLUT1 and make a direct comparison between GLUT1 and GLUT3 using both structural and functional data. Our work shows that interactions between a cytosolic Sugar Porter motif and a conserved “A motif” stabilize the outward conformational state and increases substrate affinity, while a previously undescribed Cl ion site and endofacial lipid/glucose binding site impede this interaction to modulate GLUT kinetics. The results provide an explanation for the difference between GLUT1 and GLUT3 glucose affinity, imply a general model for kinetic regulation in GLUTs and suggest a physiological function of the defining SP sequence motif in the Sugar Porter family.