ArticleThe Journal of biological chemistry2015
Mechanism of the Association between Na+ Binding and Conformations at the Intracellular Gate in Neurotransmitter:Sodium Symporters.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 52 citations in OpenAlex.
- Cytosolic KJournal of chemical theory and computation · 2026Article
- Structural basis of vilazodone dual binding mode to the serotonin transporter.Nature communications · 2025Article
- Control of Conformational Transitions by the Conserved GXInternational journal of molecular sciences · 2025Article
- Unlocking the Potential of High-Quality Dopamine Transporter Pharmacological Data: Advancing Robust Machine Learning-Based QSAR Modeling.Advances in neurobiology · 2025Review
- Substrate Binding and Conformational Dynamics of the Monoamine Transporters.Advances in neurobiology · 2025Review
- The Structural Basis of the Activity Cliff in Modafinil-Based Dopamine Transporter Inhibitors.Biomolecules · 2024Article
- General principles of secondary active transporter function.Biophysics reviews · 2022Review
- Sodium Binding Stabilizes the Outward-Open State of SERT by Limiting Bundle Domain Motions.Cells · 2022Article
- Article
- Insight into the direct interaction of NaScientific reports · 2021Article
- Exploring the putative mechanism of allosteric modulations by mixed-action kappa/mu opioid receptor bitopic modulators.Future medicinal chemistry · 2021Article
- The fine art of preparing membrane transport proteins for biomolecular simulations: Concepts and practical considerations.Methods (San Diego, Calif.) · 2021Review
- Investigating the Mechanism of Sodium Binding to SERT Using Direct Simulations.Frontiers in cellular neuroscience · 2021Article
- Locking Two Rigid-body Bundles in an Outward-Facing Conformation: The Ion-coupling Mechanism in a LeuT-fold Transporter.Scientific reports · 2019Article
- Computation-guided analysis of paroxetine binding to hSERT reveals functionally important structural elements and dynamics.Neuropharmacology · 2019Article
- Bases of Bacterial Sodium Channel Selectivity Among Organic Cations.Scientific reports · 2019Article
- PySFD: comprehensive molecular insights from significant feature differences detected among many simulated ensembles.Bioinformatics (Oxford, England) · 2019Article
- The LeuT-fold neurotransmitter:sodium symporter MhsT has two substrate sites.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Exploring Substrate Binding in the Extracellular Vestibule of MhsT by Atomistic Simulations and Markov Models.Journal of chemical information and modeling · 2018Article
- Competition between LiChemical science · 2018Article
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Authors and funding
11 authors at 5 institutions in 3 countries.
Funding
Abstract
Neurotransmitter:sodium symporters (NSSs) terminate neurotransmission by Na(+)-dependent reuptake of released neurotransmitters. Previous studies suggested that Na(+)-binding reconfigures dynamically coupled structural elements in an allosteric interaction network (AIN) responsible for function-related conformational changes, but the intramolecular pathway of this mechanism has remained uncharted. We describe a new approach for the modeling and analysis of intramolecular dynamics in the bacterial NSS homolog LeuT. From microsecond-scale molecular dynamics simulations and cognate experimental verifications in both LeuT and human dopamine transporter (hDAT), we apply the novel method to identify the composition and the dynamic properties of their conserved AIN. In LeuT, two different perturbations disrupting Na(+) binding and transport (i.e. replacing Na(+) with Li(+) or the Y268A mutation at the intracellular gate) affect the AIN in strikingly similar ways. In contrast, other mutations that affect the intracellular gate (i.e. R5A and D369A) do not significantly impair Na(+) cooperativity and transport. Our analysis shows these perturbations to have much lesser effects on the AIN, underscoring the sensitivity of this novel method to the mechanistic nature of the perturbation. Notably, this set of observations holds as well for hDAT, where the aligned Y335A, R60A, and D436A mutations also produce different impacts on Na(+) dependence. Thus, the detailed AIN generated from our method is shown to connect Na(+) binding with global conformational changes that are critical for the transport mechanism. That the AIN between the Na(+) binding sites and the intracellular gate in bacterial LeuT resembles that in eukaryotic hDAT highlights the conservation of allosteric pathways underlying NSS function.
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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.