ArticleBiophysical journal2022
The substrate import mechanism of the human serotonin transporter.
Article in Biophysical journal, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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19 citing papers in PubMed, 50 citations in OpenAlex.
- Neurotropic potential and docking investigations of newly synthesized triazolopyridine and triazolothienopyridine derivatives.RSC advances · 2026Article
- TRACT assay-based in vitro characterization of substituted cathinones: inhibition and release at the serotonin transporter.Archives of toxicology · 2026Article
- Beyond neurotransmission: the roles of serotonylation in physiological and pathological processes.Cellular & molecular biology letters · 2026Review
- Article
- Advanced Computational Methods in Protein Simulations: A Case Study of Enhanced Sampling Applied to Membrane Transporters.Advances in experimental medicine and biology · 2026Review
- How minor sequence changes enable mechanistic diversity in MFS transporters? An atomic-level rationale for symport emergence in NarU.bioRxiv : the preprint server for biology · 2025Article
- Unveiling the Structure of PROT and ATBMolecules (Basel, Switzerland) · 2025Article
- An Orchestrated Interaction Network at the Binding Site of Human SERT Enables the Serotonin Occlusion and Import.Biochemistry · 2025Article
- Energetics of substrate transport in proton-dependent oligopeptide transporters.Communications chemistry · 2024Article
- APACE: AlphaFold2 and advanced computing as a service for accelerated discovery in biophysics.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- The Arabidopsis AtSWEET13 transporter discriminates sugars by selective facial and positional substrate recognition.Communications biology · 2024Article
- Identification of the potassium-binding site in serotonin transporter.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Ligand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors.Nature communications · 2024Article
- Oligomerization of Monoamine Transporters.Sub-cellular biochemistry · 2024Review
- Probing binding and occlusion of substrate in the human creatine transporter-1 by computation and mutagenesis.Protein science : a publication of the Protein Society · 2024Article
- Dynamic extracellular vestibule of human SERT: Unveiling druggable potential with high-affinity allosteric inhibitors.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Activation mechanism of the human Smoothened receptor.Biophysical journal · 2023Article
- The Bright Side of Psychedelics: Latest Advances and Challenges in Neuropharmacology.International journal of molecular sciences · 2023Review
- Recent Advances in Machine Learning Variant Effect Prediction Tools for Protein Engineering.Industrial & engineering chemistry research · 2022Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The serotonin transporter (SERT) initiates the reuptake of extracellular serotonin in the synapse to terminate neurotransmission. The cryogenic electron microscopy structures of SERT bound to ibogaine and the physiological substrate serotonin resolved in different states have provided a glimpse of the functional conformations at atomistic resolution. However, the conformational dynamics and structural transitions to intermediate states are not fully understood. Furthermore, the molecular basis of how serotonin is recognized and transported remains unclear. In this study, we performed unbiased microsecond-long simulations of the human SERT to investigate the structural dynamics to various intermediate states and elucidated the complete substrate import pathway. Using Markov state models, we characterized a sequential order of conformational-driven ion-coupled substrate binding and transport events and calculated the free energy barriers of conformation transitions associated with the import mechanism. We find that the transition from the occluded to inward-facing state is the rate-limiting step for substrate import and that the substrate decreases the free energy barriers to achieve the inward-facing state. Our study provides insights on the molecular basis of dynamics-driven ion-substrate recognition and transport of SERT that can serve as a model for other closely related neurotransmitter transporters.
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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.