title: Major human gamma-aminobutyrate transporter: in silico prediction of substrate efficacy.
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.
authors.affiliation: Department of Neurochemistry, Chemical Research Center, Hungarian Academy of Sciences, H-1025 Pusztaszeri út 59-67, Budapest, Hungary.
authors.forename: Anna
authors.initials: A
authors.lastname: Palló
authors.forename: Akos
authors.initials: A
authors.lastname: Bencsura
authors.forename: László
authors.initials: L
authors.lastname: Héja
authors.forename: Tamás
authors.initials: T
authors.lastname: Beke
authors.forename: András
authors.initials: A
authors.lastname: Perczel
authors.forename: Julianna
authors.initials: J
authors.lastname: Kardos
authors.forename: Agnes
authors.initials: A
authors.lastname: Simon
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D050485:GABA Plasma Membrane Transport Proteins / Q000737:chemistry* / Q000648:ultrastructure*; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D013379:Substrate Specificity; D005680:gamma-Aminobutyric Acid / Q000737:chemistry*
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; C493413:SLC6A1 protein, human; D005680:gamma-Aminobutyric Acid