ArticleBiophysical journal2012
Ion-controlled conformational dynamics in the outward-open transition from an occluded state of LeuT.
Article in Biophysical journal, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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Who cites it
64 citing papers in PubMed.
- Structure-guided development of a potent human BCommunications biology · 2026Article
- Substrate Binding and Conformational Dynamics of the Monoamine Transporters.Advances in neurobiology · 2025Review
- Monitoring conformational changes in the human neurotransmitter transporter homologue LeuT withJournal of neurochemistry · 2025Article
- SWEET family transporters act as water conducting carrier proteins in plants.bioRxiv : the preprint server for biology · 2024Article
- The Structural Basis of the Activity Cliff in Modafinil-Based Dopamine Transporter Inhibitors.Biomolecules · 2024Article
- Sodium Binding Stabilizes the Outward-Open State of SERT by Limiting Bundle Domain Motions.Cells · 2022Article
- The Lepidopteran KAAT1 and CAATCH1: Orthologs to Understand Structure-Function Relationships in Mammalian SLC6 Transporters.Neurochemical research · 2022Article
- Heteromeric Solute Carriers: Function, Structure, Pathology and Pharmacology.Advances in experimental medicine and biology · 2021Review
- Investigating the Mechanism of Sodium Binding to SERT Using Direct Simulations.Frontiers in cellular neuroscience · 2021Article
- The fine art of preparing membrane transport proteins for biomolecular simulations: Concepts and practical considerations.Methods (San Diego, Calif.) · 2021Review
- The Amino Terminus of LeuT Changes Conformation in an Environment Sensitive Manner.Neurochemical research · 2020Article
- Mapping of Ion and Substrate Binding Sites in Human Sodium Iodide Symporter (hNIS).Journal of chemical information and modeling · 2020Article
- X-ray structure of LeuT in an inward-facing occluded conformation reveals mechanism of substrate release.Nature communications · 2020Article
- A structural basis for how ligand binding site changes can allosterically regulate GPCR signaling and engender functional selectivity.Science signaling · 2020Article
- Locking Two Rigid-body Bundles in an Outward-Facing Conformation: The Ion-coupling Mechanism in a LeuT-fold Transporter.Scientific reports · 2019Article
- Serotonin transport in the 21st century.The Journal of general physiology · 2019Review
- The allosteric mechanism of substrate-specific transport in SLC6 is mediated by a volumetric sensor.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Article
- Conformational transitions of the sodium-dependent sugar transporter, vSGLT.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- The Isomeric Preference of an Atypical Dopamine Transporter Inhibitor Contributes to Its Selection of the Transporter Conformation.ACS chemical neuroscience · 2017Article
4 more citing papers are in PubMed but not listed here.
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6 authors.
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Abstract
Neurotransmitter:sodium symporter (NSS) proteins are secondary Na(+)-driven active transporters that terminate neurotransmission by substrate uptake. Despite the availability of high-resolution crystal structures of a bacterial homolog of NSSs-Leucine Transporter (LeuT)-and extensive computational and experimental structure-function studies, unanswered questions remain regarding the transport mechanisms. We used microsecond atomistic molecular-dynamics (MD) simulations and free-energy computations to reveal ion-controlled conformational dynamics of LeuT in relation to binding affinity and selectivity of the more extracellularly positioned Na(+) binding site (Na1 site). In the course of MD simulations starting from the occluded state with bound Na(+), but in the absence of substrate, we find a spontaneous transition of the extracellular vestibule of LeuT into an outward-open conformation. The outward opening is enhanced by the absence of Na1 and modulated by the protonation state of the Na1-associated Glu-290. Consistently, the Na(+) affinity for the Na1 site is inversely correlated with the extent of outward-open character and is lower than in the occluded state with bound substrate; however, the Na1 site retains its selectivity for Na(+) over K(+) in such conformational transitions. To the best of our knowledge, our findings shed new light on the Na(+)-driven transport cycle and on the symmetry in structural rearrangements for outward- and inward-open transitions.
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