ArticleProceedings of the National Academy of Sciences of the United States of America2008
Mechanism for alternating access in neurotransmitter transporters.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 233 papers.
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Who cites it
233 citing papers in PubMed.
- The SLC-ome of membrane transport: from molecular discovery to physiology and clinical applications.Physiological reviews · 2026Review
- Molecular mechanisms of mitochondrial CaNature communications · 2026Article
- From extracellular entry to intracellular release: A water-assisted transport cycle for creatine in SLC6A8.Protein science : a publication of the Protein Society · 2026Article
- The Role of Cholesterol at the CHOL2 Site and the Dimeric Interface in the Regulation of Serotonin Transporter Function and Dimerization.Biomolecules · 2026Article
- Molecular mechanisms of mitochondrial CabioRxiv : the preprint server for biology · 2026Article
- Mechanisms of transport and analgesic compounds recognition by glycine transporter 2.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- A complete set of rate constants for a transporter's catalytic cycle.The Journal of general physiology · 2025Article
- Control of Conformational Transitions by the Conserved GXInternational journal of molecular sciences · 2025Article
- Dynamic energy conversion in protein catalysis: From brownian motion to enzymatic function.Computational and structural biotechnology journal · 2025Review
- Alternating access of a bacterial homolog of neurotransmitter: sodium symporters determined from AlphaFold2 ensembles and DEER spectroscopy.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Conformational free-energy landscapes of a NaProceedings of the National Academy of Sciences of the United States of America · 2024Article
- A Conserved Intramolecular Ion-Pair Plays a Critical but Divergent Role in Regulation of Dimerization and Transport Function among the Monoamine Transporters.International journal of molecular sciences · 2024Article
- Major facilitator superfamily efflux pumps in human pathogens: Role in multidrug resistance and beyond.Current research in microbial sciences · 2024Article
- Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400.The EMBO journal · 2024Article
- Functional and pathological consequences of being fast on the uptake: Protein kinase G and p38α MAPK regulation of serotonin transporters.Current research in physiology · 2024Review
- Unique Substrate Recognition and Sodium-Substrate Binding Stoichiometry in a Bacterial Serotonin Transporter, TuriSERT.International journal of molecular sciences · 2023Article
- Substrate recognition and transport mechanism of the PIN-FORMED auxin exporters.Trends in biochemical sciences · 2023Review
- Structure-based discovery of conformationally selective inhibitors of the serotonin transporter.Cell · 2023Article
- Ins and Outs of Rocker Switch Mechanism in Major Facilitator Superfamily of Transporters.Membranes · 2023Review
- Structural insights into the elevator-type transport mechanism of a bacterial ZIP metal transporter.Nature communications · 2023Article
173 more citing papers are in PubMed but not listed here.
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7 authors.
Funding
Abstract
Crystal structures of LeuT, a bacterial homologue of mammalian neurotransmitter transporters, show a molecule of bound substrate that is essentially exposed to the extracellular space but occluded from the cytoplasm. Thus, there must exist an alternate conformation for LeuT in which the substrate is accessible to the cytoplasm and a corresponding mechanism that switches accessibility from one side of the membrane to the other. Here, we identify the cytoplasmic accessibility pathway of the alternate conformation in a mammalian serotonin transporter (SERT) (a member of the same transporter family as LeuT). We also propose a model for the cytoplasmic-facing state that exploits the internal pseudosymmetry observed in the crystal structure. LeuT contains two structurally similar repeats (TMs1-5 and TMs 6-10) that are inverted with respect to the plane of the membrane. The conformational differences between them result in the formation of the extracellular pathway. Our model for the cytoplasm-facing state exchanges the conformations of the two repeats and thus exposes the substrate and ion-binding sites to the cytoplasm. The conformational change that connects the two states primarily involves the tilting of a 4-helix bundle composed of transmembrane helices 1, 2, 6, and 7. Switching the tilt angle of this bundle is essentially equivalent to switching the conformation of the two repeats. Extensive mutagenesis of SERT and accessibility measurements, using cysteine reagents, are accommodated by our model. These observations may be of relevance to other transporter families, many of which contain internal inverted repeats.
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