Assessing Structure, Function and Druggability of Major Inhibitory Neurotransmitter gamma-Aminobutyrate Symporter Subtypes

作者：Kardos J; Pallo A; Bencsura A; Simon A^*

来源：Current Medicinal Chemistry, 2010, 17(20): 2203-2213.

• LeuT structure
• Homology modeling
• Neuronal and glial GABA transporter subtypes
• Pharmacophore
• Sodium-GABA complex
• Zinc binding site

Ambient level of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter of the brain is mediated by neuronal and glial GABA transporters (GATs), members of the sodium and chloride ion-dependent solute carrier family. The neuronal GABA transporter subtype (GAT-1) has already been proven to be the target for the antiepileptic drug Tiagabine. However, druggability of glial GAT-2 and GAT-3 is yet to be established.
Recent advances in structure elucidation of a bacterial orthologue leucine transporter in complex with different substrates substantiate homology modeling of human GATs (hGATs). These modeling studies can provide mechanistic clues for structure-based prediction of the potential of medicinal chemistry campaigns. A recently identified characteristic structural feature of the occluded conformation of hGATs is that similar extra-and intracellular gates are formed by middle-broken transmembrane helices TM1 and TM6. Binding crevice formed by unwound segments of broken helices facilitates symport of GABA with Na(+) ion via fitting of GABA to TM1-bound Na(+)(1) closely inside. Favored accommodation of substrate inhibitors with high docking score predicts efficient inhibition of the neuronal hGAT-1 if the TM1-TM8 binding prerequisite for GABA was used. Docking, molecular dynamics and transport data indicate, that amino acids participating in substrate binding of the neuronal hGAT-1 and the glial hGAT-2 and hGAT-3 subtypes are different. By contrast, substrate binding crevices of hGAT-2 and hGAT-3 cannot be distinguished, avoiding sensible prediction of efficient selective substrate inhibitors. Glial subtypes might be specifically distinguished by interfering Zn(2+) binding in the second extracellular loop of hGAT-3. Formation of the unique ring-like Na(+)-GABA complex in the occluded binding crevices anticipates family member symporters exploring chemiosmotic energy via reversible chemical coupling of Na(+) ion.

• 出版日期2010-7