Glycine Transporter 2: Mechanism and Allosteric Modulation.
allosteric modulation
glycine transporter
lipid modulation
neurotransmitter sodium symporters (NSS)
solute carrier 6 (SLC6)
Journal
Frontiers in molecular biosciences
ISSN: 2296-889X
Titre abrégé: Front Mol Biosci
Pays: Switzerland
ID NLM: 101653173
Informations de publication
Date de publication:
2021
2021
Historique:
received:
01
07
2021
accepted:
25
10
2021
entrez:
22
11
2021
pubmed:
23
11
2021
medline:
23
11
2021
Statut:
epublish
Résumé
Neurotransmitter sodium symporters (NSS) are a subfamily of SLC6 transporters responsible for regulating neurotransmitter signalling. They are a major target for psychoactive substances including antidepressants and drugs of abuse, prompting substantial research into their modulation and structure-function dynamics. Recently, a series of allosteric transport inhibitors have been identified, which may reduce side effect profiles, compared to orthosteric inhibitors. Allosteric inhibitors are also likely to provide different clearance kinetics compared to competitive inhibitors and potentially better clinical outcomes. 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). Whilst the architecture of eukaryotic NSS is generally well conserved there are differences in regions that form the VAS, LAS, and CHOL1. 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.
Identifiants
pubmed: 34805268
doi: 10.3389/fmolb.2021.734427
pii: 734427
pmc: PMC8602798
doi:
Types de publication
Journal Article
Review
Langues
eng
Pagination
734427Subventions
Organisme : NIDA NIH HHS
ID : R01 DA048879
Pays : United States
Informations de copyright
Copyright © 2021 Frangos, Cantwell Chater and Vandenberg.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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