Assessing structure, function and druggability of major inhibitory neurotransmitter gamma-aminobutyrate symporter subtypes

• Published in: Current medicinal chemistry Vol. 17; no. 20; p. 2203
• Main Authors: Kardos, J, Palló, A, Bencsura, A, Simon, A
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 01-07-2010
• Subjects: Bacterial Proteins - chemistry; Bacterial Proteins - classification; Bacterial Proteins - metabolism; GABA Plasma Membrane Transport Proteins - chemistry; GABA Plasma Membrane Transport Proteins - metabolism; GABA Uptake Inhibitors; Humans; Protein Binding; Protein Structure, Tertiary; Structural Homology, Protein; Substrate Specificity; Zinc - chemistry
• ISSN: 1875-533X
• DOI: 10.2174/092986710791299939

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+ 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 Zn2+ 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.