Major human gamma-aminobutyrate transporter: in silico prediction of substrate efficacy

Anna Palló; Akos Bencsura; László Héja; Tamás Beke; András Perczel; Julianna Kardos; Agnes Simon

doi:10.1016/j.bbrc.2007.10.108

Major human gamma-aminobutyrate transporter: in silico prediction of substrate efficacy

Biochem Biophys Res Commun. 2007 Dec 28;364(4):952-8. doi: 10.1016/j.bbrc.2007.10.108. Epub 2007 Oct 29.

Authors

Anna Palló¹, Akos Bencsura, László Héja, Tamás Beke, András Perczel, Julianna Kardos, Agnes Simon

Affiliation

¹ Department of Neurochemistry, Chemical Research Center, Hungarian Academy of Sciences, H-1025 Pusztaszeri út 59-67, Budapest, Hungary.

PMID: 17967412
DOI: 10.1016/j.bbrc.2007.10.108

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Computer Simulation
GABA Plasma Membrane Transport Proteins / chemistry*
GABA Plasma Membrane Transport Proteins / ultrastructure*
Humans
Models, Chemical*
Models, Molecular*
Protein Binding
Protein Conformation
Substrate Specificity
gamma-Aminobutyric Acid / chemistry*

Substances

GABA Plasma Membrane Transport Proteins
SLC6A1 protein, human
gamma-Aminobutyric Acid