ArticleCellular and molecular life sciences : CMLS2018
Resculpting the binding pocket of APC superfamily LeuT-fold amino acid transporters.
Article in Cellular and molecular life sciences : CMLS, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 40 citations in OpenAlex.
- The SLC-ome of membrane transport: from molecular discovery to physiology and clinical applications.Physiological reviews · 2026Review
- Structure and conformational dynamics of the Pseudomonas CbrA transceptor.Protein science : a publication of the Protein Society · 2026Article
- Structure and conformational dynamics of thebioRxiv : the preprint server for biology · 2026Article
- Structural bases of signal generation and transduction by the SPS amino acid sensor of Saccharomyces cerevisiae.G3 (Bethesda, Md.) · 2026Article
- Structure-based modeling and engineering of Corynebacterium glutamicum LysE transporter for efficient extrusion of L-arginine.Communications biology · 2025Article
- Article
- Non-Steroidal Anti-Inflammatory Drugs Are Inhibitors of the Intestinal Proton-Coupled Amino Acid Transporter (PAT1): Ibuprofen and Diclofenac Are Non-Translocated Inhibitors.Pharmaceutics · 2025Article
- Structure-activity relationship of amino acid analogs to probe the binding pocket of sodium-coupled neutral amino acid transporter SNAT2.Amino acids · 2024Article
- They all rock: A systematic comparison of conformational movements in LeuT-fold transporters.Structure (London, England : 1993) · 2024Article
- Fitness landscape of substrate-adaptive mutations in evolved amino acid-polyamine-organocation transporters.eLife · 2024Article
- Phenotypic profiling of solute carriers characterizes serine transport in cancer.Nature metabolism · 2023Article
- The human LAT1-4F2hc (SLC7A5-SLC3A2) transporter complex: Physiological and pathophysiological implications.Basic & clinical pharmacology & toxicology · 2023Review
- Co-option of a conserved host glutamine transporter facilitates aphid/Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Reshaping the Binding Pocket of the Neurotransmitter:Solute Symporter (NSS) Family Transporter SLC6A14 (ATBBiomolecules · 2022Article
- Predicting the Structure and Dynamics of Membrane Protein GerAB fromInternational journal of molecular sciences · 2021Article
- Functional Characterization of the γ-Aminobutyric Acid Transporter from Mycobacterium smegmatis MCJournal of bacteriology · 2021Article
- Heteromeric Solute Carriers: Function, Structure, Pathology and Pharmacology.Advances in experimental medicine and biology · 2021Review
- Homology modeling and site-directed mutagenesis identify amino acid residues underlying the substrate selection mechanism of human monocarboxylate transporters 1 (hMCT1) and 4 (hMCT4).Cellular and molecular life sciences : CMLS · 2019Article
- Trading amino acids at the aphid-Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Genome-Wide Association Study for Milk Protein Composition Traits in a Chinese Holstein Population Using a Single-Step Approach.Frontiers in genetics · 2019Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Amino acid transporters are essential components of prokaryote and eukaryote cells, possess distinct physiological functions, and differ markedly in substrate specificity. Amino acid transporters can be both drug targets and drug transporters (bioavailability, targeting) with many monogenic disorders resulting from dysfunctional membrane transport. The largest collection of amino acid transporters (including the mammalian SLC6, SLC7, SLC32, SLC36, and SLC38 families), across all kingdoms of life, is within the Amino acid-Polyamine-organoCation (APC) superfamily. The LeuT-fold is a paradigm structure for APC superfamily amino acid transporters and carriers of sugars, neurotransmitters, electrolytes, osmolytes, vitamins, micronutrients, signalling molecules, and organic and fatty acids. Each transporter is specific for a unique sub-set of solutes, specificity being determined by how well a substrate fits into each binding pocket. However, the molecular basis of substrate selectivity remains, by and large, elusive. Using an integrated computational and experimental approach, we demonstrate that a single position within the LeuT-fold can play a crucial role in determining substrate specificity in mammalian and arthropod amino acid transporters within the APC superfamily. Systematic mutation of the amino acid residue occupying the equivalent position to LeuT V104 titrates binding pocket space resulting in dramatic changes in substrate selectivity in exemplar APC amino acid transporters including PAT2 (SLC36A2) and SNAT5 (SLC38A5). Our work demonstrates how a single residue/site within an archetypal structural motif can alter substrate affinity and selectivity within this important superfamily of diverse membrane transporters.
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