Predicting the three-dimensional structure of the human facilitative glucose transporter Glut1 by a novel evolutionary homology strategy: Insights on the molecular mechanism of substrate migration, and binding sites for glucose and inhibitory molecules

Salas Burgos A.; Iserovich, P; Zuniga, F; Vera, JC; Fischbarg, J

Abstract

The glucose transporters (GLUT/SLC2A) are members of the major facilitator superfamily. Here, we generated a three-dimensional model for Glut1 using a two-step strategy: 1), GlpT structure as an initial homology template and 2), evolutionary homology using glucose-6-phosphate translocase as a template. The resulting structure (PDB No. 1SUK) exhibits a water-filled passageway communicating the extracellular and intracellular domains, with a funnel-like exofacial vestibule (infundibulum), followed by a 15 Å-long × 8 Å-wide channel, and a horn-shaped endofacial vestibule. Most residues which, by mutagenesis, are crucial for transport delimit the channel, and putative sugar recognition motifs (QLS, QLG) border both ends of the channel. On the outside of the structure there are two positively charged cavities (one exofacial, one endofacial) delimited by ATP-binding Walker motifs, and an exofacial large side cavity of yet unknown function. Docking sites were found for the glucose substrate and its inhibitors: glucose, forskolin, and phloretin at the exofacial infundibulum; forskolin, and phloretin at an endofacial site next to the channel opening; and cytochalasin B at a positively charged endofacial pocket 3 Å away from the channel. Thus, 1SUK accounts for practically all biochemical and mutagenesis evidence, and provides clues for the transport process. © 2004 by the Biophysical Society.

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Título según WOS: Predicting the three-dimensional structure of the human facilitative glucose transporter Glut1 by a novel evolutionary homology strategy: Insights on the molecular mechanism of substrate migration, and binding sites for glucose and inhibitory molecules
Título según SCOPUS: Predicting the three-dimensional structure of the human facilitative glucose transporter Glut1 by a novel evolutionary homology strategy: Insights on the molecular mechanism of substrate migration, and binding for glucose and inhibitory molecules
Título de la Revista: BIOPHYSICAL JOURNAL
Volumen: 87
Número: 5
Editorial: Cell Press
Fecha de publicación: 2004
Página de inicio: 2990
Página final: 2999
Idioma: English
URL: http://linkinghub.elsevier.com/retrieve/pii/S0006349504737716
DOI:

10.1529/biophysj.104.047886

Notas: ISI, SCOPUS