|Title||Molecular basis of ligand recognition and transport by glucose transporters.|
|Publication Type||Journal Article|
|Year of Publication||2015|
|Authors||Deng, D, Sun, P, Yan, C, Ke, M, Jiang, X, Xiong, L, Ren, W, Hirata, K, Yamamoto, M, Fan, S, Yan, N|
|Date Published||2015 Oct 15|
|Keywords||Binding Sites, Biological Transport, Cell Membrane, Crystallography, X-Ray, Glucose, Glucose Transporter Type 1, Glucose Transporter Type 3, Humans, Kinetics, Ligands, Maltose, Models, Molecular, Protein Binding, Protein Conformation, Recombinant Proteins, Rotation, Structure-Activity Relationship|
The major facilitator superfamily glucose transporters, exemplified by human GLUT1-4, have been central to the study of solute transport. Using lipidic cubic phase crystallization and microfocus X-ray diffraction, we determined the structure of human GLUT3 in complex with D-glucose at 1.5 Å resolution in an outward-occluded conformation. The high-resolution structure allows discrimination of both α- and β-anomers of D-glucose. Two additional structures of GLUT3 bound to the exofacial inhibitor maltose were obtained at 2.6 Å in the outward-open and 2.4 Å in the outward-occluded states. In all three structures, the ligands are predominantly coordinated by polar residues from the carboxy terminal domain. Conformational transition from outward-open to outward-occluded entails a prominent local rearrangement of the extracellular part of transmembrane segment TM7. Comparison of the outward-facing GLUT3 structures with the inward-open GLUT1 provides insights into the alternating access cycle for GLUTs, whereby the C-terminal domain provides the primary substrate-binding site and the amino-terminal domain undergoes rigid-body rotation with respect to the C-terminal domain. Our studies provide an important framework for the mechanistic and kinetic understanding of GLUTs and shed light on structure-guided ligand design.
|Grant List||/ / Howard Hughes Medical Institute / United States|