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

Author(s): Salas-Burgos A, Iserovich P, Zuniga F, Vera JC, Fischbarg J


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.

Similar Articles

Membranes as possible pacemakers of metabolism

Author(s): Hulbert AJ, Else PL

Life, death and membrane bilayers

Author(s): Hulbert AJ

Quantitative atomic force microscopy with carbon monoxide terminated tips

Author(s): Sun Z, Boneschanscher MP, Swart I, Vanmaekelbergh D, Liljeroth P

Structure of lipid bilayers

Author(s): Nagle JF, Tristram-Nagle S

The cellular fate of glucose and its relevance in type 2 diabetes

Author(s): Bouché C, Serdy S, Kahn CR, Goldfine AB

Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes

Author(s): Kelley DE, He J, Menshikova EV, Ritov VB

Relationship between carnitine, fatty acids and insulin resistance

Author(s): Lohninger A, Radler U, Jinniate S, Lohninger S, Karlic H, et al.

Is irisin a human exercise gene? Nature 488: E9-10

Author(s): Timmons JA, Baar K, Davidsen PK, Atherton PJ

FNDC5 and irisin in humans: I

Author(s): Huh JY, Panagiotou G, Mougios V, Brinkoetter M, Vamvini MT, et al.

MR properties of brown and white adipose tissues

Author(s): Hamilton G, Smith DL Jr, Bydder M, Nayak KS, Hu HH

Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance

Author(s): Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, et al.

Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin

Author(s): Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, et al.

Hemorheological disorders in diabetes mellitus

Author(s): Cho YI, Mooney MP, Cho DJ

Modulation of the bilayer thickness of exocytic pathway membranes by membrane proteins rather than cholesterol

Author(s): Mitra K, Ubarretxena-Belandia I, Taguchi T, Warren G, Engelman DM