Abstract
The human facilitative transporter Glut1 is the major glucose transporter present in all human cells, has a central role in metabolism, and is an archetype of the superfamily of major protein facilitators. Here we describe a three-dimensional structure of Glut1 based on helical packing schemes proposed 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 stereochemical quality of the structure obtained were as good as those for the known structures of the KcsA K(+) channel and aquaporin 1. We found two channels in Glut1. One of them traverses the structure completely, and is lined by many residues known to be solvent-accessible. Since it is delimited by the QLS motif and by several well conserved residues, it may serve as the substrate 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 important to the transport function, we find that this Glut1 structure is consistent with mutagenesis and biochemical studies. It also accounts for functional deficits in seven pathogenic mutants.
Highlights
The facilitative glucose transporter Glut1 is perhaps the most extensively studied membrane transporter
We describe a three-dimensional structure of Glut1 based on helical packing schemes proposed for lactose permease and Glut1 and predictions of secondary structure, and refined using energy minimization, molecular dynamics simulations, and quality and environmental scores
From the locations of sugar transporter signatures, motifs, and residues important to the transport function, we find that this Glut1 structure is consistent with mutagenesis and biochemical studies
Summary
From the locations of sugar transporter signatures, motifs, and residues important to the transport function, we find that this Glut structure is consistent with mutagenesis and biochemical studies. Given the attending difficulties in crystallizing membrane proteins, there is growing interest in the development and application of molecular modeling techniques to understand the structure of Gluts and relate it to their function. The lack of crystallographic structures for most classes of membrane proteins (including Gluts) means that there are no suitable templates that can be used to generate structures by homology modeling This creates a need for alternative modeling approaches in which the available experimental biological and biophysical data are used as a reference for the modeling process. We describe here the procedures utilized and offer validation for our structure using stereochemical analysis and mutagenesis data
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