ArticleThe Journal of biological chemistry2008
Time-resolved mechanism of extracellular gate opening and substrate binding in a glutamate transporter.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 92 citations in OpenAlex.
- Conformational free energy landscape of a glutamate transporter and microscopic details of its transport mechanism.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Structural basis of the obligatory exchange mode of human neutral amino acid transporter ASCT2.Nature communications · 2024Article
- Discovery of (Journal of medicinal chemistry · 2022Article
- Linking function to global and local dynamics in an elevator-type transporter.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Critical amino acids in the TM2 of EAAT2 are essential for membrane-bound localization, substrate binding, transporter function and anion currents.Journal of cellular and molecular medicine · 2021Article
- The high-energy transition state of the glutamate transporter homologue GltPh.The EMBO journal · 2021Article
- Observing spontaneous, accelerated substrate binding in molecular dynamics simulations of glutamate transporters.PloS one · 2021Article
- Millisecond dynamics of an unlabeled amino acid transporter.Nature communications · 2020Article
- Structural ensemble of a glutamate transporter homologue in lipid nanodisc environment.Nature communications · 2020Article
- Long-range correlation in protein dynamics: Confirmation by structural data and normal mode analysis.PLoS computational biology · 2020Article
- Advances and Challenges in Rational Drug Design for SLCs.Trends in pharmacological sciences · 2019Review
- Free-Energy Simulations Resolve the Low-Affinity NaBiophysical journal · 2019Article
- Investigation of the allosteric coupling mechanism in a glutamate transporter homolog via unnatural amino acid mutagenesis.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Substrate transport and anion permeation proceed through distinct pathways in glutamate transporters.eLife · 2017Article
- TM4 of the glutamate transporter GLT-1 experiences substrate-induced motion during the transport cycle.Scientific reports · 2016Article
- Transport mechanism of a glutamate transporter homologue GltPh.Biochemical Society transactions · 2016Review
- SLC Transporters: Structure, Function, and Drug Discovery.MedChemComm · 2016Article
- Electrogenic Steps Associated with Substrate Binding to the Neuronal Glutamate Transporter EAAC1.The Journal of biological chemistry · 2016Article
- The Split Personality of Glutamate Transporters: A Chloride Channel and a Transporter.Neurochemical research · 2016Article
- Molecular physiology of EAAT anion channels.Pflugers Archiv : European journal of physiology · 2016Review
2 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Glutamate transporters, also referred to as excitatory amino acid transporters (EAATs), are membrane proteins that regulate glutamatergic signal transmission by clearing excess glutamate after its release at synapses. A structure-based understanding of their molecular mechanisms of function has been elusive until the recent determination of the x-ray structure of an archaeal transporter, Glt(Ph). Glt(Ph) exists as a trimer, with each subunit containing a core region that mediates substrate translocation. In the present study a series of molecular dynamics simulations have been conducted and analyzed in light of new experimental data on substrate binding properties of EAATs. The simulations provide for the first time a full atomic description of the time-resolved events that drive the recognition and binding of substrate. The core region of each subunit exhibits an intrinsic tendency to open the helical hairpin HP2 loop, the extracellular gate, within tens of nanoseconds exposing conserved polar residues that serve as attractors for substrate binding. The NMDGT motif on the partially unwound part of the transmembrane helix TM7 and the residues Asp-390 and Asp-394 on TM8 are also distinguished by their important role in substrate binding and close interaction with mediating water molecules and/or sodium ions. The simulations reveal a Na+ binding site comprised in part of Leu-303 on TM7 and Asp-405 on TM8 and support a role for sodium ions in stabilizing substrate-bound conformers. The functional importance of Leu-303 or its counterpart Leu-391 in human EAAT1 (hEAAT1) is confirmed by site-directed mutagenesis and Na+ dependence assays conducted with hEAAT1 mutants L391C and L391A.
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Registered trials
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.