Insights into substrate and inhibitor selectivity among human GLUT transporters through comparative modeling and molecular docking

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Ferreira, Rafaela Salgado | Pons, Jean-Luc | Labesse, Gilles

Edité par CCSD ; ACS Publications -

International audience. The SLC2 family is composed of 14 transporters, which are members of the major facilitator superfamily (MFS). Despite their high physiological importance, there are still many open questions concerning their function and specificity, and in some cases, their physiological substrate is still unknown. To understand the determinants of substrate and inhibitor specificity, here we modeled all human GLUTs and simulated their interaction with known ligands. Comparative modeling was performed with the @TOME-2 pipeline, employing multiple templates and providing an ensemble of models for each GLUT. We analyzed models in both outward-occluded and inward-open conformations, to compare exofacial and endofacial binding sites throughout the family and understand differences in susceptibility of GLUTs to the inhibitor cytochalasin B.

Finally, we employed molecular docking and bioinformatics to identify residues likely critical for recognition of myo-inositol by GLUT13 and urate by GLUT9, providing insights into the molecular basis for the specificity for these substrates. In addition, we suggested a potential recognition of glucosamine by GLUT11 to be evaluated in future experiment.

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