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
Volume385
Issue2
Pagination210-4
Date Published2009 Jul 24
ISSN1090-2104
KeywordsAllosteric Regulation, Amino Acid Motifs, Crystallography, GABA Plasma Membrane Transport Proteins, gamma-Aminobutyric Acid, Humans, Models, Molecular, Protein Binding, Protein Conformation, Sodium, Zinc
Abstract

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.

DOI10.1016/j.bbrc.2009.05.040
Alternate JournalBiochem. Biophys. Res. Commun.
PubMed ID19450549