Substrate-Na{sup +} complex formation: Coupling mechanism for {gamma}-aminobutyrate symporters

Journal Article · Fri Jul 24 04:00:00 EDT 2009 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2009.05.040· OSTI ID:22199745

Pallo, Anna; Simon, Agnes ^[1]; Bencsura, Akos ^[2]; Heja, Laszlo ^[1]; Kardos, Julianna ^[1]

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1. Department of Neurochemistry, Institute of Biomolecular Chemistry, Chemical Research Center, Hungarian Academy of Sciences (Hungary)
2. Department of Theoretical Chemistry, Institute of Structural Chemistry, Chemical Research Center, Hungarian Academy of Sciences, Budapest (Hungary)

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{sup +} 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{sup 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{sup +} ion. The existence of the minor ring-like conformation of {gamma}-aminobutyric acid in complex with Na{sup +} ion may be attributed to the strengthening of the intramolecular H-bond by the electrostatic effect of Na{sup +} ion. Coupling substrate uptake into cells with the thermodynamically favorable Na{sup +} ion movement through substrate-Na{sup +} ion complex formation may be a mechanistic principle featuring transmembrane neurotransmitter-sodium symporter proteins.

• OSTI ID: 22199745
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 2 Vol. 385; ISSN BBRCA9; ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
AMINOBUTYRIC ACID
COUPLING
CRYSTAL STRUCTURE
INDIUM COMPLEXES
MOLECULAR DYNAMICS METHOD
PROTEINS
SIMULATION
SODIUM
SODIUM IONS
SUBSTRATES
UPTAKE
ZINC IONS
ZWITTERIONIC COMPOUNDS