Emerging structure-function relationships defining monoamine NSS transporter substrate and ligand affinity

Wang, Ching-I Anderson and Lewis, Richard J. (2010) Emerging structure-function relationships defining monoamine NSS transporter substrate and ligand affinity. Biochemical Pharmacology, 79 8: 1083-1091. doi:10.1016/j.bcp.2009.11.019

Author Wang, Ching-I Anderson
Lewis, Richard J.
Title Emerging structure-function relationships defining monoamine NSS transporter substrate and ligand affinity
Journal name Biochemical Pharmacology   Check publisher's open access policy
ISSN 0006-2952
Publication date 2010-04-15
Sub-type Article (original research)
DOI 10.1016/j.bcp.2009.11.019
Volume 79
Issue 8
Start page 1083
End page 1091
Total pages 9
Editor S. J. Enna
Place of publication Philadelphia, U.S.A.
Publisher Elsevier
Collection year 2011
Language eng
Subject C1
970106 Expanding Knowledge in the Biological Sciences
030599 Organic Chemistry not elsewhere classified
Formatted abstract
Monoamine transporters are a group of transmembrane neurotransmitter sodium symporter (NSS) transporters that play a crucial role in regulating biogenic monoamine concentrations at peripheral and central synapses. Given the key role played by serotonin, dopamine and noradrenaline in addictive and disease states, structure–function studies have been conducted to help guide the development of improved central nervous system therapeutics. Extensive pharmacological, immunological and biochemical studies, in conjunction with three-dimensional homology modeling, have been performed to structurally and functionally characterise themonoamine transporter substrate permeation pathway, substrate selectivity, and binding sites for ions, substrates and inhibitors at the molecular level. However, only recently has it been possible to start to construct an accurate molecular interaction network for the monoamine transporters and their corresponding substrates and inhibitors. Crystal structures of Aquifex aeolicus leucine transporter (LeuTAa), a homologous protein to monoamine transporters that has been experimentally demonstrated to share similar structural folds with monoamine transporters, have been determined in complex with amino acids and inhibitors. The molecular interactions of leucine and tricyclic antidepressants (TCA) has supported many of the predictions based on the mutational studies. Models constructed from LeuTAa are now allowing a rational approach to further clarify the molecular determinants of NSS transporter–ligand complexes, and potentially the ability to better manipulate drug specificity and affinity. In this review, we compare the structure–function relationships of other SLC6 NSS family transporters with monoamine transporters, and discuss possible mechanisms involved in substrate binding and transport, and modes of inhibition by TCAs.
Crown Copyright © 2009 Published by Elsevier Inc. All rights reserved.
Keyword Leucine transporter
Monoamine transporter
Homology models
Structure-function relationship
Tricyclic antidepressant
Na+/Cl- binding sites
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2010 Higher Education Research Data Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 10 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 15 times in Scopus Article | Citations
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Created: Sun, 28 Mar 2010, 00:07:02 EST