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Glycine Transporter 2: Mechanism and Allosteric Modulation
Zachary J Frangos1, Ryan P Cantwell Chater1, Robert J Vandenberg1
1Transporter Biology Group, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
Frontiers in Molecular Biosciences
|November 22, 2021
Summary
Neurotransmitter sodium symporters (NSS) are key targets for drugs. New allosteric inhibitors offer potential for improved efficacy and reduced side effects by targeting specific binding sites like VAS, LAS, and CHOL1.
Area of Science:
- Biochemistry
- Neuroscience
- Pharmacology
Background:
- Neurotransmitter sodium symporters (NSS) regulate neurotransmission and are targets for psychoactive drugs.
- Allosteric inhibitors are emerging as a potentially safer alternative to orthosteric inhibitors, offering different pharmacokinetic profiles.
Purpose of the Study:
- To explore ligand-protein interactions at allosteric sites on NSS.
- To investigate exploiting structural differences for developing NSS-specific compounds, focusing on GlyT2.
Main Methods:
- Analysis of crystal structures and homology models of NSS.
- Characterization of ligand binding at the vestibule allosteric site (VAS), lipid allosteric site (LAS), and cholesterol binding site (CHOL1).
Main Results:
- Identified distinct allosteric modulatory sites (VAS, LAS, CHOL1) on eukaryotic NSS.
- Described ligand-protein interactions stabilizing binding within these sites.
- Highlighted conserved and divergent regions across NSS that form these allosteric sites.
Conclusions:
- Allosteric sites on NSS offer opportunities for developing targeted therapeutics.
- Exploiting structural variations in VAS, LAS, and CHOL1 can lead to selective GlyT2 modulators.
- Allosteric inhibition may provide improved clinical outcomes compared to traditional inhibitors.
Keywords:
allosteric modulationglycine transporterlipid modulationneurotransmitter sodium symporters (NSS)solute carrier 6 (SLC6)More Related Videos
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