ArticleProceedings of the National Academy of Sciences of the United States of America2022
Molecular determinants of inhibition of the human proton channel hHv1 by the designer peptide C6 and a bivalent derivative.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 15 citations in OpenAlex.
- A designer pore-blocking peptide reveals an electrostatic complementation mechanism for the inhibition-resistant Kv1.5 channel.Science advances · 2026Article
- Amyloid precursor protein is a subunit of microglial Hv1 channels.Current opinion in immunology · 2026Review
- Microglial HVCN1 Deficiency Improves Movement and Survival of SOD1Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Toward the rational design of oncogenic TASK-3 channel inhibitor peptides and nanoconjugate complexes.Frontiers in pharmacology · 2026Review
- C6 peptide blockade of Hv1 channels inhibits neutrophil migration into the lungs to suppress Pseudomonas aeruginosa-induced acute lung injury.Respiratory research · 2025Article
- Amyloid precursor protein and C99 are subunits in human microglial Hv1 channels that enhance current and inflammatory mediator release.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Modulators of the Human Voltage-Gated Proton Channel HPharmaceuticals (Basel, Switzerland) · 2025Review
- Hv1 channel in immune cells and pharmacology.Pharmacological research · 2025Review
- Validation of HvFrontiers in cellular neuroscience · 2025Article
- Design of Ultrapotent Genetically Encoded Inhibitors of Kv4.2 for Gating Neural Plasticity.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Role of the Voltage-Gated Proton Channel Hv1 in Nervous Systems.Neuroscience bulletin · 2023Review
- 5-Chloro-2-Guanidinobenzimidazole (ClGBI) Is a Non-Selective Inhibitor of the Human HPharmaceuticals (Basel, Switzerland) · 2023Article
- Protection from acute lung injury by a peptide designed to inhibit the voltage-gated proton channel.iScience · 2023Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
The human voltage-gated proton channel (hHv1) is important for control of intracellular pH. We designed C6, a specific peptide inhibitor of hHv1, to evaluate the roles of the channel in sperm capacitation and in the inflammatory immune response of neutrophils [R. Zhao et al., Proc. Natl. Acad. Sci. U.S.A. 115, E11847–E11856 (2018)]. One C6 binds with nanomolar affinity to each of the two S3–S4 voltage-sensor loops in hHv1 in cooperative fashion so that C6-bound channels require greater depolarization to open and do so more slowly. As depolarization drives hHv1 sensors outwardly, C6 affinity decreases, and inhibition is partial. Here, we identified residues essential to C6–hHv1 binding by scanning mutagenesis, five in the hHv1 S3–S4 loops and seven on C6. A structural model of the C6–hHv1 complex was then generated by molecular dynamics simulations and validated by mutant-cycle analysis. Guided by this model, we created a bivalent C6 peptide (C62) that binds simultaneously to both hHv1 subunits and fully inhibits current with picomolar affinity. The results help delineate the structural basis for C6 state-dependent inhibition, support an anionic lipid-mediated binding mechanism, and offer molecular insight into the effectiveness of engineered C6 as a therapeutic agent or lead.
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Registered trials
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