THE TRANSPORTER 2 SERIES

The mechanism of transport has largely been inferred from crystal structures of the Aquifex aeolicus bacterial leucine transporter (LeuT) and supplemented by recently solved structures of the eukaryotic Drosophila melanogaster dopamine transporter (dDAT), human serotonin (hSERT) and human glycine transporter type 1 (hGlyT1) ( Yamashita et al., 2005 Penmatsa et al., 2013 Wang et al., 2015 Coleman et al., 2016 Shahsavar et al., 2021). The role of NSS in the etiology of these conditions highlights the importance of understanding the structure-function dynamics of this family and how they can be modulated for therapeutic purposes. Impaired functions of these transporters have been implicated in a variety of neurological disorders including addiction, depression, epilepsy, hyperekplexia, neuropathic pain, Parkinson’s disease, and schizophrenia ( Benarroch, 2011 Benarroch, 2013). Members of the solute carrier 6 (SLC6) family act on a broad range of neurotransmitter substrates: glycine (GlyTs), dopamine (DAT), serotonin (SERT), noradrenaline (NET) and γ-aminobutyric acid (GABA, GAT) ( Amara and Kuhar, 1993 Kristensen et al., 2011). Neurotransmitter sodium symporters (NSS) are secondary active transporters that regulate synaptic concentrations of neurotransmitters via reuptake into surrounding glial cells or presynaptic terminals. Here, we describe ligand-protein interactions that stabilize binding in each allosteric site and explore how differences between transporters could be exploited to generate NSS specific compounds with an emphasis on GlyT2 modulation. Whilst the architecture of eukaryotic NSS is generally well conserved there are differences in regions that form the VAS, LAS, and CHOL1. Crystal structures and homology models have identified several allosteric modulatory sites on NSS including the vestibule allosteric site (VAS), lipid allosteric site (LAS) and cholesterol binding site (CHOL1). Allosteric inhibitors are also likely to provide different clearance kinetics compared to competitive inhibitors and potentially better clinical outcomes.

THE TRANSPORTER 2 SERIES

Recently, a series of allosteric transport inhibitors have been identified, which may reduce side effect profiles, compared to orthosteric inhibitors. They are a major target for psychoactive substances including antidepressants and drugs of abuse, prompting substantial research into their modulation and structure-function dynamics. Neurotransmitter sodium symporters (NSS) are a subfamily of SLC6 transporters responsible for regulating neurotransmitter signalling. Transporter Biology Group, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.

The transporter 2