ArticlePharmaceutical research2024
Inhibitory Potential of the Truncated Isoforms on Glutamate Transporter Oligomerization Identified by Computational Analysis of Gene-Centric Isoform Maps.
Article in Pharmaceutical research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- In silico directed evolution of humanized peptide transporters via computational epistatic rescue.Molecular diversity · 2026Article
- Dynamics-aware evolutionary profiling uncouples structural rigidity from functional motion to enable enhanced variant interpretation.Functional & integrative genomics · 2026Article
- Integrative Structural Bioinformatics and Molecular Dynamics Analyses of Synaptic Vesicle Proteins and Their Water-Soluble QTY-Variants Reveal Membrane Constraints and Evolutionary Coupling of T ⇔ V.Journal of molecular evolution · 2026Article
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4 authors.
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Abstract
objectiveGlutamate transporters play a key role in central nervous system physiology by maintaining excitatory neurotransmitter homeostasis. Biological assemblies of the transporters, consisting of cyclic homotrimers, emerge as a crucial aspect of glutamate transporter modulation. Hence targeting heteromerization promises an effective approach for modulator design. On the other hand, the dynamic nature of transcription allows for the generation of transporter isoforms in structurally distinct manners.
methodsThe potential isoforms were identified through the analysis of computationally generated gene-centric isoform maps. The conserved features of isoform sequences were revealed by computational chemistry methods and subsequent structural analysis of AlphaFold2 predictions. Truncated isoforms were further subjected to a wide range of docking analyses, 50ns molecular dynamics simulations, and evolutionary coupling analyses.
resultsEnergetic landscapes of isoform-canonical transporter complexes suggested an inhibitory potential of truncated isoforms on glutamate transporter bio-assembly. Moreover, isoforms that mimic the trimerization domain (in particular, TM2 helices) exhibited stronger interactions with canonical transporters, underscoring the role of transmembrane helices in isoform interactions. Additionally, self-assembly dynamics observed in truncated isoforms mimicking canonical TM5 helices indicate a potential protective role against unwanted interactions with canonical transporters.
conclusionOur computational studies on glutamate transporters offer insights into the roles of alternative splicing on protein interactions and identifies potential drug targets for physiological or pathological processes.
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