Major human γ-aminobutyrate transporter: In silico prediction of substrate efficacy

Anna Palló, Ákos Bencsura, László Héja, Tamás Beke, András Perczel, Julianna Kardos, Ágnes Simon

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

The inhibitory γ-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-β-Pro, (R)-nipecotic acid, and guvacine. It might therefore represent the principle, sufficient for sorting out less-effective or non-GAT ligands such as β-Pro, (S)-nipecotic acid, (R)-baclofen, Glu, and Leu.

Original languageEnglish
Pages (from-to)952-958
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume364
Issue number4
DOIs
Publication statusPublished - Dec 28 2007

Keywords

  • Crystal structure-based homology modeling
  • Effective conformation
  • Human transporter
  • Molecular dynamics
  • Substrate docking
  • γ-Aminobutyrate

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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