Molecular modelling of gamma-aminobutyric acid transport: Zn2+ binding to the transporter and formation of Na+(1)-GABA complex.
-
1
Department of Neurochemistry, Institute of Biomolecular Chemistry, Hungary
-
2
Department of Theoretical Chemistry, Institute of Structural Chemistry, Hungary
The major inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is removed from the extracellular space by integral membrane proteins, belonging to the solute carrier 6 (SLC6) family of sodium-coupled transporters, also known as neurotransmitter sodium symporters. Certain pathological conditions, including epilepsy can be treated by inhibition of the neuronal GABA transporter functions. Based on structural information at atomic resolution available for a bacterial homologue (LeuTAa), models of the occluded conformational state of the human neuronal (hGAT-1) and glial (hGAT-2 and hGAT-3) GABA transporters were built. Models were validated by docking a selected set of transportable substrates and inhibitors (ligands), and by subsequent molecular dynamics (MD) calculations. All docked ligands were found to interact with one of the two sodium ions Na+(1) proved to be essential for substrate-binding. The conformation of GABA was changed during MD calculations, resulting in a ring structure formed by intramolecular H-bonding between amino and carboxyl groups, the latter being in a strong electrostatic interaction with Na+(1), suggesting that hGAT-1, hGAT-2 and hGAT-3 may transport GABA in complex with Na+(1). Unraveling the zinc binding sites possibly present in the extracellular loops and negatively charged regions of the membrane-embedded helices of hGAT-2 and hGAT-3 is intimately linked to the goal of elucidating their distinguishable zinc ion-sensitivity and to the development of new antiepileptic agents in the future.
Conference:
12th Meeting of the Hungarian Neuroscience Society, Budapest, Hungary, 22 Jan - 24 Jan, 2009.
Presentation Type:
Poster Presentation
Topic:
Developmental neurobiology and subcortical functions
Citation:
Pallo
A,
Simon
Á,
Bencsura
A,
Heja
L and
Kardos
J
(2009). Molecular modelling of gamma-aminobutyric acid transport: Zn2+ binding to the transporter and formation of Na+(1)-GABA complex..
Front. Syst. Neurosci.
Conference Abstract:
12th Meeting of the Hungarian Neuroscience Society.
doi: 10.3389/conf.neuro.01.2009.04.072
Copyright:
The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers.
They are made available through the Frontiers publishing platform as a service to conference organizers and presenters.
The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated.
Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed.
For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions.
Received:
02 Mar 2009;
Published Online:
02 Mar 2009.
*
Correspondence:
Ágnes Simon, Department of Neurochemistry, Institute of Biomolecular Chemistry, Budapest, Hungary, simonagi@chemres.hu