ArticlePloS one2013
A potent and selective peptide blocker of the Kv1.3 channel: prediction from free-energy simulations and experimental confirmation.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed.
- Voltage-Gated KMarine drugs · 2024Review
- Alchemical Free Energy Calculations on Membrane-Associated Proteins.Journal of chemical theory and computation · 2023Review
- Genomic, functional and structural analyses elucidate evolutionary innovation within the sea anemone 8 toxin family.BMC biology · 2023Article
- Article
- Adeno-Associated virus 8 delivers an immunomodulatory peptide to mouse liver more efficiently than to rat liver.PloS one · 2023Article
- Modelling peptide-protein complexes: docking, simulations and machine learning.QRB discovery · 2022Article
- Kv1.3 voltage-gated potassium channels link cellular respiration to proliferation through a non-conducting mechanism.Cell death & disease · 2021Article
- Article
- Long-term obesogenic diet and targeted deletion of potassium channel KPhysiological reports · 2019Article
- Rapid and accurate structure-based therapeutic peptide design using GPU accelerated thermodynamic integration.Proteins · 2019Article
- A Recurrent Motif: Diversity and Evolution of ShKT Domain Containing Proteins in the Vampire SnailToxins · 2019Article
- Review
- Prolonged immunomodulation in inflammatory arthritis using the selective Kv1.3 channel blocker HsTX1[R14A] and its PEGylated analog.Clinical immunology (Orlando, Fla.) · 2017Article
- Molecular Simulations of Disulfide-Rich Venom Peptides with Ion Channels and Membranes.Molecules (Basel, Switzerland) · 2017Review
- Biobetters From an Integrated Computational/Experimental Approach.Computational and structural biotechnology journal · 2017Review
- A computational approach for designing D-proteins with non-canonical amino acid optimised binding affinity.PloS one · 2017Article
- Preferential uptake of antioxidant carbon nanoparticles by T lymphocytes for immunomodulation.Scientific reports · 2016Article
- Accurate Prediction of Ligand Affinities for a Proton-Dependent Oligopeptide Transporter.Cell chemical biology · 2016Article
- Study of Small-Molecule-Membrane Protein Binding Kinetics with Nanodisc and Charge-Sensitive Optical Detection.Analytical chemistry · 2016Article
- Review
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Authors and funding
10 authors.
Funding
Abstract
The voltage-gated potassium channel Kv1.3 is a well-established target for treatment of autoimmune diseases. ShK peptide from a sea anemone is one of the most potent blockers of Kv1.3 but its application as a therapeutic agent for autoimmune diseases is limited by its lack of selectivity against other Kv channels, in particular Kv1.1. Accurate models of Kv1.x-ShK complexes suggest that specific charge mutations on ShK could considerably enhance its specificity for Kv1.3. Here we evaluate the K18A mutation on ShK, and calculate the change in binding free energy associated with this mutation using the path-independent free energy perturbation and thermodynamic integration methods, with a novel implementation that avoids convergence problems. To check the accuracy of the results, the binding free energy differences were also determined from path-dependent potential of mean force calculations. The two methods yield consistent results for the K18A mutation in ShK and predict a 2 kcal/mol gain in Kv1.3/Kv1.1 selectivity free energy relative to wild-type peptide. Functional assays confirm the predicted selectivity gain for ShK[K18A] and suggest that it will be a valuable lead in the development of therapeutics for autoimmune diseases.
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Registered trials
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