ArticleProceedings of the National Academy of Sciences of the United States of America2009
Molecular simulations elucidate the substrate translocation pathway in a glutamate transporter.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 50 citations in OpenAlex.
- From extracellular entry to intracellular release: A water-assisted transport cycle for creatine in SLC6A8.Protein science : a publication of the Protein Society · 2026Article
- 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
- 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
- Observing spontaneous, accelerated substrate binding in molecular dynamics simulations of glutamate transporters.PloS one · 2021Article
- Molecular dynamics simulations informed by membrane lipidomics reveal the structure-interaction relationship of polymyxins with the lipid A-based outer membrane of Acinetobacter baumannii.The Journal of antimicrobial chemotherapy · 2020Article
- 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
- Caver Web 1.0: identification of tunnels and channels in proteins and analysis of ligand transport.Nucleic acids research · 2019Article
- Molecular Dynamics Simulation for All.Neuron · 2018Review
- Analysis of the quality of crystallographic data and the limitations of structural models.The Journal of general physiology · 2017Review
- Substrate transport and anion permeation proceed through distinct pathways in glutamate transporters.eLife · 2017Article
- Article
- SLC Transporters: Structure, Function, and Drug Discovery.MedChemComm · 2016Article
- Long range recognition and selection in IDPs: the interactions of the C-terminus of p53.Scientific reports · 2016Article
- Chloride requirement for monoamine transporters.Pflugers Archiv : European journal of physiology · 2016Review
- A current view of serotonin transporters.F1000Research · 2016Review
- The Hydroxyl Side Chain of a Highly Conserved Serine Residue Is Required for Cation Selectivity and Substrate Transport in the Glial Glutamate Transporter GLT-1/SLC1A2.The Journal of biological chemistry · 2015Article
- Computational Studies of Glutamate Transporters.Biomolecules · 2015Review
- Refinement of the Central Steps of Substrate Transport by the Aspartate Transporter GltPh: Elucidating the Role of the Na2 Sodium Binding Site.PLoS computational biology · 2015Article
- New look at hemoglobin allostery.Chemical reviews · 2015Review
- Article
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
Glutamate transporters are membrane proteins found in neurons and glial cells, which play a critical role in regulating cell signaling by clearing glutamate released from synapses. Although extensive biochemical and structural studies have shed light onto different aspects of glutamate transport, the time-resolved molecular mechanism of substrate (glutamate or aspartate) translocation, that is, the sequence of events occurring at the atomic level after substrate binding and before its release intracellularly remain to be elucidated. We identify an energetically preferred permeation pathway of approximately 23 A between the helix HP1b on the hairpin HP1 and the transmembrane helices TM7 and TM8, using the high resolution structure of the transporter from Pyrococcus horikoshii (Glt(Ph)) in steered molecular dynamics simulations. Detailed potential of mean force calculations along the putative pathway reveal 2 energy barriers encountered by the substrate (aspartate) before it reaches the exit. The first barrier is surmounted with the assistance of 2 conserved residues (S278 and N401) and a sodium ion (Na2); and the second, by the electrostatic interactions with D405 and another sodium ion (Na1). The observed critical interactions and mediating role of conserved residues in the core domain, the accompanying conformational changes (in both substrate and transporter) that relieve local strains, and the unique coupling of aspartate transport to Na(+) dislocation provide insights into methods for modulating substrate 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.