Title | Major human gamma-aminobutyrate transporter: in silico prediction of substrate efficacy. |
Publication Type | Journal Article |
Year of Publication | 2007 |
Authors | Palló, A., A. Bencsura, L. Héja, T. Beke, A. Perczel, J. Kardos, and A. Simon |
Journal | Biochem Biophys Res Commun |
Volume | 364 |
Issue | 4 |
Pagination | 952-8 |
Date Published | 2007 Dec 28 |
ISSN | 1090-2104 |
Keywords | Binding Sites, Computer Simulation, GABA Plasma Membrane Transport Proteins, gamma-Aminobutyric Acid, Humans, Models, Chemical, Models, Molecular, Protein Binding, Protein Conformation, Substrate Specificity |
Abstract | The inhibitory gamma-aminobutyric acid transporter subtype 1 (GAT1) maintains low resting synaptic GABA level, and is a potential target for antiepileptic drugs. Here we report a high scored binding mode that associates GABA with gating in a homology model of the human GAT1. Docking and molecular dynamics calculations recognize the amino function of GABA in the H-bonding state favoring TM1 and TM8 helix residues Y60 and S396, respectively. This ligand binding mode visibly ensures the passage of GABA and substrate inhibitors (R)-homo-beta-Pro, (R)-nipecotic acid, and guvacine. It might therefore represent the principle, sufficient for sorting out less-effective or non-GAT ligands such as beta-Pro, (S)-nipecotic acid, (R)-baclofen, Glu, and Leu. |
DOI | 10.1016/j.bbrc.2007.10.108 |
Alternate Journal | Biochem. Biophys. Res. Commun. |
PubMed ID | 17967412 |
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