ArticleACS chemical neuroscience2015
Spontaneous inward opening of the dopamine transporter is triggered by PIP2-regulated dynamics of the N-terminus.
Article in ACS chemical neuroscience, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers.
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Who cites it
72 citing papers in PubMed, 104 citations in OpenAlex.
- Multicolor Quantum Dot Tracking Uncovers Phenotypic Rescue of DAT A559V Aberrant Diffusion Upon D2R Antagonism.ACS chemical neuroscience · 2026Article
- The Influence of Phosphoinositide Lipids in the Molecular Biology of Membrane Proteins: Recent Insights from Simulations.Journal of molecular biology · 2025Review
- The Structural Basis of the Activity Cliff in Modafinil-Based Dopamine Transporter Inhibitors.Biomolecules · 2024Article
- Comprehensive Characterization of LAT1 Cholesterol-Binding Sites.Journal of chemical theory and computation · 2024Article
- Targeting SLC transporters: small molecules as modulators and therapeutic opportunities.Trends in biochemical sciences · 2023Review
- The solute carrier SPNS2 recruits PI(4,5)PMolecular cell · 2023Article
- Phosphatidylinositol 4,5-bisphosphate (PIPCommunications biology · 2022Article
- Conformational transitions in BTG1 antiproliferative protein and their modulation by disease mutants.Biophysical journal · 2022Article
- Molecular determinants of pH sensing in the proton-activated chloride channel.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Effects of the N-terminal dynamics on the conformational states of human dopamine transporter.Biophysical chemistry · 2022Article
- Allosteric Modulator KM822 Attenuates Behavioral Actions of Amphetamine inMolecular pharmacology · 2022Article
- The substrate import mechanism of the human serotonin transporter.Biophysical journal · 2022Article
- Molecular mechanisms of action of stimulant novel psychoactive substances that target the high-affinity transporter for dopamine.Neuronal signaling · 2021Review
- A network of phosphatidylinositol (4,5)-bisphosphate (PIPMolecular psychiatry · 2021Article
- Localization atomic force microscopy.Nature · 2021Article
- Ligand-Dependent Conformational Transitions in Molecular Dynamics Trajectories of GPCRs Revealed by a New Machine Learning Rare Event Detection Protocol.Molecules (Basel, Switzerland) · 2021Article
- Article
- The fine art of preparing membrane transport proteins for biomolecular simulations: Concepts and practical considerations.Methods (San Diego, Calif.) · 2021Review
- 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
12 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
We present the dynamic mechanism of concerted motions in a full-length molecular model of the human dopamine transporter (hDAT), a member of the neurotransmitter/sodium symporter (NSS) family, involved in state-to-state transitions underlying function. The findings result from an analysis of unbiased atomistic molecular dynamics simulation trajectories (totaling >14 μs) of the hDAT molecule immersed in lipid membrane environments with or without phosphatidylinositol 4,5-biphosphate (PIP2) lipids. The N-terminal region of hDAT (N-term) is shown to have an essential mechanistic role in correlated rearrangements of specific structural motifs relevant to state-to-state transitions in the hDAT. The mechanism involves PIP2-mediated electrostatic interactions between the N-term and the intracellular loops of the transporter molecule. Quantitative analyses of collective motions in the trajectories reveal that these interactions correlate with the inward-opening dynamics of hDAT and are allosterically coupled to the known functional sites of the transporter. The observed large-scale motions are enabled by specific reconfiguration of the network of ionic interactions at the intracellular end of the protein. The isomerization to the inward-facing state in hDAT is accompanied by concomitant movements in the extracellular vestibule and results in the release of an Na(+) ion from the Na2 site and destabilization of the substrate dopamine in the primary substrate binding S1 site. The dynamic mechanism emerging from the findings highlights the involvement of the PIP2-regulated interactions between the N-term and the intracellular loop 4 in the functionally relevant conformational transitions that are also similar to those found to underlie state-to-state transitions in the leucine transporter (LeuT), a prototypical bacterial homologue of the NSS.
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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.