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

Authors :
Ákos Bencsura
Julianna Kardos
Ágnes Simon
László Héja
Anna Palló
Source :
Biochemical and biophysical research communications. 385(2)
Publication Year :
2009

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.

Details

ISSN :
10902104
Volume :
385
Issue :
2
Database :
OpenAIRE
Journal :
Biochemical and biophysical research communications
Accession number :
edsair.doi.dedup.....2c32b300e889e1bc30a3b267166ebc2a