ArticlePLoS computational biology2015
Refinement of the Central Steps of Substrate Transport by the Aspartate Transporter GltPh: Elucidating the Role of the Na2 Sodium Binding Site.
Article in PLoS computational biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- On the Role of a Conserved Methionine in the NaNeurochemical research · 2022Article
- Observing spontaneous, accelerated substrate binding in molecular dynamics simulations of glutamate transporters.PloS one · 2021Article
- Computational Dissection of Membrane Transport at a Microscopic Level.Trends in biochemical sciences · 2020Review
- Kinetic Models of Secondary Active Transporters.International journal of molecular sciences · 2019Article
- Advances and Challenges in Rational Drug Design for SLCs.Trends in pharmacological sciences · 2019Review
- Free-Energy Simulations Resolve the Low-Affinity NaBiophysical journal · 2019Article
- Both reentrant loops of the sodium-coupled glutamate transporters contain molecular determinants of cation selectivity.The Journal of biological chemistry · 2018Article
- Analysis of the quality of crystallographic data and the limitations of structural models.The Journal of general physiology · 2017Review
- Characterisation of the DAACS Family Escherichia coli Glutamate/Aspartate-Proton Symporter GltP Using Computational, Chemical, Biochemical and Biophysical Methods.The Journal of membrane biology · 2017Article
- Coupled binding mechanism of three sodium ions and aspartate in the glutamate transporter homologue GltNature communications · 2016Article
- Transport mechanism of a glutamate transporter homologue GltPh.Biochemical Society transactions · 2016Review
- SLC Transporters: Structure, Function, and Drug Discovery.MedChemComm · 2016Article
- Computational Studies of Glutamate Transporters.Biomolecules · 2015Review
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Authors and funding
8 authors.
Funding
Abstract
Glutamate homeostasis in the brain is maintained by glutamate transporter mediated accumulation. Impaired transport is associated with several neurological disorders, including stroke and amyotrophic lateral sclerosis. Crystal structures of the homolog transporter GltPh from Pyrococcus horikoshii revealed large structural changes. Substrate uptake at the atomic level and the mechanism of ion gradient conversion into directional transport remained enigmatic. We observed in repeated simulations that two local structural changes regulated transport. The first change led to formation of the transient Na2 sodium binding site, triggered by side chain rotation of T308. The second change destabilized cytoplasmic ionic interactions. We found that sodium binding to the transiently formed Na2 site energized substrate uptake through reshaping of the energy hypersurface. Uptake experiments in reconstituted proteoliposomes confirmed the proposed mechanism. We reproduced the results in the human glutamate transporter EAAT3 indicating a conserved mechanics from archaea to humans.
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