ArticleMolecular cell2008
The mechanism of a neurotransmitter:sodium symporter--inward release of Na+ and substrate is triggered by substrate in a second binding site.
Article in Molecular cell, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 256 papers.
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Who cites it
256 citing papers in PubMed, 383 citations in OpenAlex.
- Cooperative mechanism of neurotransmitter recognition and transport by the human vesicular polyamine transporter.Nature communications · 2026Article
- From extracellular entry to intracellular release: A water-assisted transport cycle for creatine in SLC6A8.Protein science : a publication of the Protein Society · 2026Article
- Identification of Small-Molecule Inhibitors that Block the GTP-Binding Pocket of K-Ras and Other Members of the Ras Superfamily of Small GTPases.Molecular cancer therapeutics · 2026Article
- Revealing the location and dynamics of a concealed binding site in the dopamine transporter.Nature communications · 2025Article
- Exploring the Structural Dynamics of LeuT Using EPR Spectroscopy: A Focus on Transmembrane Helix 10.Journal of neurochemistry · 2025Article
- Adding salt to foods and risk of incident depression and anxiety.BMC medicine · 2025Article
- The conserved lysine residue in transmembrane helix 5 is pivotal for the cytoplasmic gating of the L-amino acid transporters.PNAS nexus · 2025Article
- Novel Ways of Targeting the Dopamine Transporter.Advances in neurobiology · 2025Review
- Fluorescent non-canonical amino acid provides insight into the human serotonin transporter.Nature communications · 2024Article
- Molecular basis of inhibition of the amino acid transporter BNature communications · 2024Article
- The Structural Basis of the Activity Cliff in Modafinil-Based Dopamine Transporter Inhibitors.Biomolecules · 2024Article
- Exploring the KeLife · 2024Article
- Mechanism of anion exchange and small-molecule inhibition of pendrin.Nature communications · 2024Article
- Allosteric modulation of serotonin and dopamine transporters: New insights from computations and experiments.Current research in physiology · 2024Article
- Cholesterol modulation of interactions between psychostimulants and dopamine transporters.Advances in pharmacology (San Diego, Calif.) · 2024Article
- Regulation of Ebola GP conformation and membrane binding by the chemical environment of the late endosome.PLoS pathogens · 2023Article
- Implications for Combination Therapy of Selective Monoamine Reuptake Inhibitors on Dopamine Transporters.Biomedicines · 2023Article
- Dynamic extracellular vestibule of human SERT: Unveiling druggable potential with high-affinity allosteric inhibitors.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Atorvastatin differentially regulates the interactions of cocaine and amphetamine with dopamine transporters.Neuropharmacology · 2023Article
- Do Amino Acid Antiporters Have Asymmetric Substrate Specificity?Biomolecules · 2023Article
196 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
Eukaryotic neurotransmitter:sodium symporters (NSSs), targets for antidepressants and psychostimulants, terminate neurotransmission by sodium-driven reuptake. The crystal structure of LeuT(Aa), a prokaryotic NSS homolog, revealed an occluded state in which one leucine and two Na(+) ions are bound, but provided limited clues to the molecular mechanism of transport. Using steered molecular dynamics simulations, we explored the substrate translocation pathway of LeuT. We identified a second substrate binding site located in the extracellular vestibule comprised of residues shown recently to participate in binding tricyclic antidepressants. Binding and flux experiments showed that the two binding sites can be occupied simultaneously. The substrate in the secondary site allosterically triggers intracellular release of Na(+) and substrate from the primary site, thereby functioning as a "symport effector." Because tricyclic antidepressants bind differently to this secondary site, they do not promote substrate release from the primary site and thus act as symport uncouplers and inhibit transport.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.