A molecular model of the three-dimensional (3-D) structure of the glucose transport protein, GLUT3, has been derived by homology modeling. The model was built on the basis of structural data from the MscL protein, which is a mechanosensitive ion channel, and general insights from aquaporin (a water permeation pore). Structurally conserved regions were defined by amino acid sequence comparisons, optimum interconnecting loops were selected from the protein databank, and amino (N)- and carboxy (C)-terminal ends of the protein were generated as random coil structures. The model was then subjected to energy minimization and molecular dynamics simulations in the presence of bound substrate (D-glucose). In the proposed structure of GLUT3, the 12 transmembrane (TM) helices form a right-hand barrel with a central hydrophilic pore. The pore is shaped like a funnel with dimensions of approximately 5-6 A by 8 A at its narrowest point. A network of polar and aromatic amino acids line the pore region and may facilitate the movement of glucose along the channel. A putative binding site for inhibitory ligands, such as forskolin and cytochalasin B, was identified on an intracellular aspect of the protein. Molecular dynamics studies showed that changes in the tilt and flexibility of key TM helices may modulate the opening of the pore to effect glucose transport. The proposed structure of GLUT3 may prove useful in guiding future experiments aimed at more precisely defining various functional regions of the transporter and may encourage efforts to develop models of other complex membrane proteins.