ArticlePNAS nexus2022
Apo and ligand-bound high resolution Cryo-EM structures of the human Kv3.1 channel reveal a novel binding site for positive modulators.
Article in PNAS nexus, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
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Who cites it
16 citing papers in PubMed, 1 synthesis or guideline pooled it, 19 citations in OpenAlex.
- KFrontiers in pharmacology · 2026Pooled it
- Voltage-sensor conformational microenvironments encode isoform-selective ion channel activation.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Optimization of Pyrazole-Based Activators of Kv3.1.ACS medicinal chemistry letters · 2026Article
- Structural basis for the subtype-selectivity of KNature communications · 2026Article
- Ion Channel-Targeting Toxins: Structural Mechanisms of Activation, Inhibition, and Therapeutic Potential.Toxins · 2025Review
- Recent advances in the pharmacology of voltage-gated ion channels.Pharmacological reviews · 2025Review
- Structural insights into the function, dysfunction and modulation of Kv3 channels.Neuropharmacology · 2025Review
- Voltage sensors.Molecular pharmacology · 2025Review
- Structural biology and molecular pharmacology of voltage-gated ion channels.Nature reviews. Molecular cell biology · 2024Review
- Structural basis for inhibition of the lysosomal two-pore channel TPC2 by a small molecule antagonist.Structure (London, England : 1993) · 2024Article
- The binding and mechanism of a positive allosteric modulator of Kv3 channels.Nature communications · 2024Article
- Voltage-gated potassium channels as a potential therapeutic target for the treatment of neurological and psychiatric disorders.Frontiers in cellular neuroscience · 2024Review
- Identification, structural, and biophysical characterization of a positive modulator of human Kv3.1 channels.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Targeting ion channels with ultra-large library screening for hit discovery.Frontiers in molecular neuroscience · 2023Review
- Cryo-EM structure of the human Kv3.1 channel reveals gating control by the cytoplasmic T1 domain.Nature communications · 2022Article
- Timing is everything: structural insights into the disease-linked Kv3 channels controlling fast action-potential firing in the brain.Nature communications · 2022Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Kv3 ion-channels constitute a class of functionally distinct voltage-gated ion channels characterized by their ability to fire at a high frequency. Several disease relevant mutants, together with biological data, suggest the importance of this class of ion channels as drug targets for CNS disorders, and several drug discovery efforts have been reported. Despite the increasing interest for this class of ion channels, no structure of a Kv3 channel has been reported yet. We have determined the cryo-EM structure of Kv3.1 at 2.6 Å resolution using full-length wild type protein. When compared to known structures for potassium channels from other classes, a novel domain organization is observed with the cytoplasmic T1 domain, containing a well-resolved Zinc site and displaying a rotation by 35°. This suggests a distinct cytoplasmic regulation mechanism for the Kv3.1 channel. A high resolution structure was obtained for Kv3.1 in complex with a novel positive modulator Lu AG00563. The structure reveals a novel ligand binding site for the Kv class of ion channels located between the voltage sensory domain and the channel pore, a region which constitutes a hotspot for disease causing mutations. The discovery of a novel binding site for a positive modulator of a voltage-gated potassium channel could shed light on the mechanism of action for these small molecule potentiators. This finding could enable structure-based drug design on these targets with high therapeutic potential for the treatment of multiple CNS disorders.
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