ArticleProceedings of the National Academy of Sciences of the United States of America2017
Conformational dynamics of a neurotransmitter:sodium symporter in a lipid bilayer.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed.
- Probing protein-lipid interactions by hydrogen/deuterium exchange-mass spectrometry: advances, challenges and future directions.Chemical science · 2026Review
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- Ins and Outs of Rocker Switch Mechanism in Major Facilitator Superfamily of Transporters.Membranes · 2023Review
- Hydrogen/deuterium exchange-mass spectrometry of integral membrane proteins in native-like environments: current scenario and the way forward.Essays in biochemistry · 2023Article
- Online Fully Automated System for Hydrogen/Deuterium-Exchange Mass Spectrometry with Millisecond Time Resolution.Analytical chemistry · 2023Article
- Structure-Based Function and Regulation of NCX Variants: Updates and Challenges.International journal of molecular sciences · 2022Review
- Determining Ligand and Ion-Induced Conformational Changes in Serotonin Transporter with Its Fluorescent Substrates.International journal of molecular sciences · 2022Article
- Integrated AlphaFold2 and DEER investigation of the conformational dynamics of a pH-dependent APC antiporter.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Advances in Hydrogen/Deuterium Exchange Mass Spectrometry and the Pursuit of Challenging Biological Systems.Chemical reviews · 2022Review
- The substrate import mechanism of the human serotonin transporter.Biophysical journal · 2022Article
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- Imaging Membrane Order and Dynamic Interactions in Living Cells with a DNA Zipper Probe.Angewandte Chemie (International ed. in English) · 2022Article
- Modeling the native ensemble of PhuS using enhanced sampling MD and HDX-ensemble reweighting.Biophysical journal · 2021Article
- Principles of Alternating Access in Multidrug and Toxin Extrusion (MATE) Transporters.Journal of molecular biology · 2021Review
- Assessing the Role of Lipids in the Molecular Mechanism of Membrane Proteins.International journal of molecular sciences · 2021Review
- Insights into substrate recognition and specificity for IgG by Endoglycosidase S2.PLoS computational biology · 2021Article
- Chloride-dependent conformational changes in the GlyT1 glycine transporter.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Probing Protein-Membrane Interactions and Dynamics Using Hydrogen-Deuterium Exchange Mass Spectrometry (HDX-MS).Methods in molecular biology (Clifton, N.J.) · 2021Article
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6 authors.
Funding
Abstract
Neurotransmitter:sodium symporters (NSSs) are integral membrane proteins responsible for the sodium-dependent reuptake of small-molecule neurotransmitters from the synaptic cleft. The symporters for the biogenic amines serotonin (SERT), dopamine (DAT), and norepinephrine (NET) are targets of multiple psychoactive agents, and their dysfunction has been implicated in numerous neuropsychiatric ailments. LeuT, a thermostable eubacterial NSS homolog, has been exploited as a model protein for NSS members to canvass the conformational mechanism of transport with a combination of X-ray crystallography, cysteine accessibility, and solution spectroscopy. Despite yielding remarkable insights, these studies have primarily been conducted with protein in the detergent-solubilized state rather than embedded in a membrane mimic. In addition, solution spectroscopy has required site-specific labeling of nonnative cysteines, a labor-intensive process occasionally resulting in diminished transport and/or binding activity. Here, we overcome these limitations by reconstituting unlabeled LeuT in phospholipid bilayer nanodiscs, subjecting them to hydrogen-deuterium exchange coupled with mass spectrometry (HDX-MS), and facilitating interpretation of the data with molecular dynamics simulations. The data point to changes of accessibility and dynamics of structural elements previously implicated in the transport mechanism, in particular transmembrane helices (TMs) 1a and 7 as well as extracellular loops (ELs) 2 and 4. The results therefore illuminate the value of this strategy for interrogating the conformational mechanism of the more clinically significant mammalian membrane proteins including SERT and DAT, neither of which tolerates complete removal of endogenous cysteines, and whose activity is heavily influenced by neighboring lipids.
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