ArticleThe Journal of biological chemistry2012
High selectivity of the γ-aminobutyric acid transporter 2 (GAT-2, SLC6A13) revealed by structure-based approach.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 47 citations in OpenAlex.
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- GABA signaling enforces intestinal germinal center B cell differentiation.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Structural insights into GABA transport inhibition using an engineered neurotransmitter transporter.The EMBO journal · 2022Article
- Gut-inhabiting Clostridia build human GPCR ligands by conjugating neurotransmitters with diet- and human-derived fatty acids.Nature microbiology · 2021Article
- Human neurons from Christianson syndrome iPSCs reveal mutation-specific responses to rescue strategies.Science translational medicine · 2021Article
- Studies of structural determinants of substrate binding in the Creatine Transporter (CreaT, SLC6A8) using molecular models.Scientific reports · 2020Article
- Homology Modeling Informs Ligand Discovery for the Glutamine Transporter ASCT2.Frontiers in chemistry · 2018Article
- Probing the changes in gene expression due to α-crystallin mutations in mouse models of hereditary human cataract.PloS one · 2018Article
- Inhibitor Discovery for the Human GLUT1 from Homology Modeling and Virtual Screening.ACS chemical biology · 2016Article
- SLC Transporters: Structure, Function, and Drug Discovery.MedChemComm · 2016Article
- Selank Administration Affects the Expression of Some Genes Involved in GABAergic Neurotransmission.Frontiers in pharmacology · 2016Article
- Ligand Discovery for the Alanine-Serine-Cysteine Transporter (ASCT2, SLC1A5) from Homology Modeling and Virtual Screening.PLoS computational biology · 2015Article
- Structure-Based Identification of Inhibitors for the SLC13 Family of Na(+)/Dicarboxylate Cotransporters.Biochemistry · 2015Article
- SLC transporters as therapeutic targets: emerging opportunities.Nature reviews. Drug discovery · 2015Review
- The physiological role of drug transporters.Protein & cell · 2015Review
- A binding mode hypothesis of tiagabine confirms liothyronine effect on γ-aminobutyric acid transporter 1 (GAT1).Journal of medicinal chemistry · 2015Article
- A pharmacogenetic candidate gene study of tenofovir-associated Fanconi syndrome.Pharmacogenetics and genomics · 2015Article
- Artificial neural network cascade identifies multi-P450 inhibitors in natural compounds.PeerJ · 2015Article
- Structural dynamics of the monoamine transporter homolog LeuT from accelerated conformational sampling and channel analysis.Proteins · 2014Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
The solute carrier 6 (SLC6) is a family of ion-dependent transporters that mediate uptake into the cell of osmolytes such as neurotransmitters and amino acids. Four SLC6 members transport GABA, a key neurotransmitter that triggers inhibitory signaling pathways via various receptors (e.g., GABA(A)). The GABA transporters (GATs) regulate the concentration of GABA available for signaling and are thus targeted by a variety of anticonvulsant and relaxant drugs. Here, we characterize GAT-2, a transporter that plays a role in peripheral GABAergic mechanisms, by constructing comparative structural models based on crystallographic structures of the leucine transporter LeuT. Models of GAT-2 in two different conformations were constructed and experimentally validated, using site-directed mutagenesis. Computational screening of 594,166 compounds including drugs, metabolites, and fragment-like molecules from the ZINC database revealed distinct ligands for the two GAT-2 models. 31 small molecules, including high scoring compounds and molecules chemically related to known and predicted GAT-2 ligands, were experimentally tested in inhibition assays. Twelve ligands were found, six of which were chemically novel (e.g., homotaurine). Our results suggest that GAT-2 is a high selectivity/low affinity transporter that is resistant to inhibition by typical GABAergic inhibitors. Finally, we compared the binding site of GAT-2 with those of other SLC6 members, including the norepinephrine transporter and other GATs, to identify ligand specificity determinants for this family. Our combined approach may be useful for characterizing interactions between small molecules and other membrane proteins, as well as for describing substrate specificities in other protein families.
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