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

TitleMajor human gamma-aminobutyrate transporter: in silico prediction of substrate efficacy.
Publication TypeJournal Article
Year of Publication2007
AuthorsPalló, A., A. Bencsura, L. Héja, T. Beke, A. Perczel, J. Kardos, and A. Simon
JournalBiochem Biophys Res Commun
Volume364
Issue4
Pagination952-8
Date Published2007 Dec 28
ISSN1090-2104
KeywordsBinding 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.

DOI10.1016/j.bbrc.2007.10.108
Alternate JournalBiochem. Biophys. Res. Commun.
PubMed ID17967412