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.
Biophys J
; 87(5): 2990-9, 2004 Nov.
Article
em En
| MEDLINE
| ID: mdl-15326030
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 A-long x 8 A-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 A away from the channel. Thus, 1SUK accounts for practically all biochemical and mutagenesis evidence, and provides clues for the transport process.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Transporte de Monossacarídeos
/
Modelos Moleculares
/
Glucose
Tipo de estudo:
Evaluation_studies
/
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Biophys J
Ano de publicação:
2004
Tipo de documento:
Article
País de afiliação:
Estados Unidos