Title | Substrate-Na+ complex formation: coupling mechanism for gamma-aminobutyrate symporters. |
Publication Type | Journal Article |
Year of Publication | 2009 |
Authors | Palló, A., A. Simon, A. Bencsura, L. Héja, and J. Kardos |
Journal | Biochem Biophys Res Commun |
Volume | 385 |
Issue | 2 |
Pagination | 210-4 |
Date Published | 2009 Jul 24 |
ISSN | 1090-2104 |
Keywords | Allosteric 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. |
DOI | 10.1016/j.bbrc.2009.05.040 |
Alternate Journal | Biochem. Biophys. Res. Commun. |
PubMed ID | 19450549 |
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