Substrate-Na+ complex formation: coupling mechanism for gamma-aminobutyrate symporters.

TitleSubstrate-Na+ complex formation: coupling mechanism for gamma-aminobutyrate symporters.
Publication TypeJournal Article
Year of Publication2009
AuthorsPalló, A., A. Simon, A. Bencsura, L. Héja, and J. Kardos
JournalBiochem Biophys Res Commun
Date Published2009 Jul 24
KeywordsAllosteric Regulation, Amino Acid Motifs, Crystallography, GABA Plasma Membrane Transport Proteins, gamma-Aminobutyric Acid, Humans, Models, Molecular, Protein Binding, Protein Conformation, Sodium, Zinc

Crystal structures of transmembrane transport proteins belonging to the important families of neurotransmitter-sodium symporters reveal how they transport neurotransmitters across membranes. Substrate-induced structural conformations of gated neurotransmitter-sodium symporters have been in the focus of research, however, a key question concerning the mechanism of Na(+) ion coupling remained unanswered. Homology models of human glial transporter subtypes of the major inhibitory neurotransmitter gamma-aminobutyric acid were built. In accordance with selectivity data for subtype 2 vs. 3, docking and molecular dynamics calculations suggest similar orthosteric substrate (inhibitor) conformations and binding crevices but distinguishable allosteric Zn(2+) ion binding motifs. Considering the occluded conformational states of glial human gamma-aminobutyric acid transporter subtypes, we found major semi-extended and minor ring-like conformations of zwitterionic gamma-aminobutyric acid in complex with Na(+) ion. The existence of the minor ring-like conformation of gamma-aminobutyric acid in complex with Na(+) ion may be attributed to the strengthening of the intramolecular H-bond by the electrostatic effect of Na(+) ion. Coupling substrate uptake into cells with the thermodynamically favorable Na(+) ion movement through substrate-Na(+) ion complex formation may be a mechanistic principle featuring transmembrane neurotransmitter-sodium symporter proteins.

Alternate JournalBiochem. Biophys. Res. Commun.
PubMed ID19450549