ArticleThe EMBO journal2022
Structural insights into GABA transport inhibition using an engineered neurotransmitter transporter.
Article in The EMBO journal, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 27 citations in OpenAlex.
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- Macromolecular crystallography at Elettra: current and future perspectives.Journal of synchrotron radiation · 2025Article
- Molecular basis of human GABA transporter 3 inhibition.Nature communications · 2025Article
- Structural Features of Coumarin-1,2,4-Triazole Hybrids Important for Insecticidal Effects AgainstMolecules (Basel, Switzerland) · 2025Article
- Insomnia treatment based on the regulation of the GABAergic system: traditional Chinese medicine perspectives and therapeutic approaches.Frontiers in neuroscience · 2025Review
- Pharmacological Mechanisms of SLC6 Neurotransmitter Transporter Inhibition.Advances in neurobiology · 2025Review
- Cryo-EM structure of the dopamine transporter with a novel atypical non-competitive inhibitor bound to the orthosteric site.Journal of neurochemistry · 2024Article
- Serotonin Signaling through Lipid Membranes.ACS chemical neuroscience · 2024Review
- Allosteric modulation of serotonin and dopamine transporters: New insights from computations and experiments.Current research in physiology · 2024Article
- Clustering Heterogeneous Conformational Ensembles of Intrinsically Disordered Proteins with t-Distributed Stochastic Neighbor Embedding.Journal of chemical theory and computation · 2023Article
- Cryo-EM structure of GABA transporter 1 reveals substrate recognition and transport mechanism.Nature structural & molecular biology · 2023Article
- Determination of Multiple Neurotransmitters through LC-MS/MS to Confirm the Therapeutic Effects ofMolecules (Basel, Switzerland) · 2023Article
- A comparative review on the well-studied GAT1 and the understudied BGT-1 in the brain.Frontiers in physiology · 2023Review
- Article
- Structural insights into GABA transport inhibition using an engineered neurotransmitter transporter.The EMBO journal · 2022Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter, and its levels in the synaptic space are controlled by the GABA transporter isoforms (GATs). GATs are structurally related to biogenic amine transporters but display interactions with distinct inhibitors used as anti-epileptics. In this study, we engineer the binding pocket of Drosophila melanogaster dopamine transporter to resemble GAT1 and determine high-resolution X-ray structures of the modified transporter in the substrate-free state and in complex with GAT1 inhibitors NO711 and SKF89976a that are analogs of tiagabine, a medication prescribed for the treatment of partial seizures. We observe that the primary binding site undergoes substantial shifts in subsite architecture in the modified transporter to accommodate the two GAT1 inhibitors. We also observe that SKF89976a additionally interacts at an allosteric site in the extracellular vestibule, yielding an occluded conformation. Interchanging SKF89976a interacting residue in the extracellular loop 4 between GAT1 and dDAT suggests a role for this motif in the selective control of neurotransmitter uptake. Our findings, therefore, provide vital insights into the organizational principles dictating GAT1 activity and inhibition.
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