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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

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

Author(s): J. Kardos, A. Pallo, A. Bencsura and A. Simon

Volume 17 , Issue 20 , 2010

Page: [2203 - 2213] Pages: 11

DOI: 10.2174/092986710791299939

Price: $65

Abstract

Ambient level of γ-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 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.

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


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