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

Anna Palló, A. Bencsura, László Héja, Tamás Beke, A. Perczel, J. Kardos, A. 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

Fingerprint

Aminobutyrates
Computer Simulation
gamma-Aminobutyric Acid
Substrates
Ligands
Baclofen
Molecular Dynamics Simulation
Sorting
Anticonvulsants
Molecular dynamics
nipecotic acid

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Major human γ-aminobutyrate transporter : In silico prediction of substrate efficacy. / Palló, Anna; Bencsura, A.; Héja, László; Beke, Tamás; Perczel, A.; Kardos, J.; Simon, A.

In: Biochemical and Biophysical Research Communications, Vol. 364, No. 4, 28.12.2007, p. 952-958.

Research output: Contribution to journalArticle

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