A three-dimensional model of the human facilitative glucose transporter Glut1

The human facilitative transporter Glut1 is the major glucose transporter p resent in all human cells, has a central role in metabolism, and is an arch etype of the superfamily of major protein facilitators. Here we describe a three-dimensional structure of Glut1 based on helical packing schemes propo sed for lactose permease and Glut1 and predictions of secondary structure, and refined using energy minimization, molecular dynamics simulations, and quality and environmental scores. The Ramachandran scores and the stereoche mical quality of the structure obtained were as good as those for the known structures of the KesA K+ channel and aquaporin 1. We found two channels i n Glut1. One of them traverses the structure completely, and is lined by ma ny residues known to be solvent-accessible. Since it is delimited by the QL S motif and by several well conserved residues, it may serve as the substra te transport pathway. To validate our structure, we determined the distance between these channels and all the residues for which mutations are known. From the locations of sugar transporter signatures, motifs, and residues i mportant to the transport function, we find that this Glut1 structure is co nsistent with mutagenesis and biochemical studies. It also accounts for fun ctional deficits in seven pathogenic mutants.