ArticleProceedings of the National Academy of Sciences of the United States of America2020
Voltage-dependent structural models of the human Hv1 proton channel from long-timescale molecular dynamics simulations.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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23 citing papers in PubMed, 39 citations in OpenAlex.
- 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
- Fluctuating hydrogen-bond network of the Hv1 ion channel.Computational and structural biotechnology journal · 2025Article
- Proton reactions: From basic science to biomedical applications.Biophysical journal · 2024Article
- Interior pH-sensing residue of human voltage-gated proton channel HBiophysical journal · 2024Article
- Quantitative insights into the mechanism of proton conduction and selectivity for the human voltage-gated proton channel Hv1.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Identification of a Novel Structural Class of HJournal of chemical information and modeling · 2024Article
- Trapping Charge Mechanism in Hv1 Channels (International journal of molecular sciences · 2023Article
- Alchemical Free Energy Calculations on Membrane-Associated Proteins.Journal of chemical theory and computation · 2023Review
- NaInternational journal of molecular sciences · 2023Review
- Fifty years of gating currents and channel gating.The Journal of general physiology · 2023Review
- Molecular determinants of inhibition of the human proton channel hHv1 by the designer peptide C6 and a bivalent derivative.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Inhibiting Hv1 channel in peripheral sensory neurons attenuates chronic inflammatory pain and opioid side effects.Cell research · 2022Article
- Gating Mechanism of the Voltage-Gated Proton Channel Studied by Molecular Dynamics Simulations.Molecules (Basel, Switzerland) · 2022Article
- Structural dynamics determine voltage and pH gating in human voltage-gated proton channel.eLife · 2022Article
- Structure of the ancient TRPY1 channel from Saccharomyces cerevisiae reveals mechanisms of modulation by lipids and calcium.Structure (London, England : 1993) · 2022Article
- A novel Hv1 inhibitor reveals a new mechanism of inhibition of a voltage-sensing domain.The Journal of general physiology · 2021Article
- HIFs: New arginine mimic inhibitors of the Hv1 channel with improved VSD-ligand interactions.The Journal of general physiology · 2021Article
- Direct activation of the proton channel by albumin leads to human sperm capacitation and sustained release of inflammatory mediators by neutrophils.Nature communications · 2021Article
- Structural Mechanism of ω-Currents in a Mutated Kv7.2 Voltage Sensor Domain from Molecular Dynamics Simulations.Journal of chemical information and modeling · 2021Article
- Voltage-gated proton channels from fungi highlight role of peripheral regions in channel activation.Communications biology · 2021Article
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Authors and funding
9 authors at 2 institutions in 2 countries.
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Abstract
The voltage-gated Hv1 proton channel is a ubiquitous membrane protein that has roles in a variety of cellular processes, including proton extrusion, pH regulation, production of reactive oxygen species, proliferation of cancer cells, and increased brain damage during ischemic stroke. A crystal structure of an Hv1 construct in a putative closed state has been reported, and structural models for the channel open state have been proposed, but a complete characterization of the Hv1 conformational dynamics under an applied membrane potential has been elusive. We report structural models of the Hv1 voltage-sensing domain (VSD), both in a hyperpolarized state and a depolarized state resulting from voltage-dependent conformational changes during a 10-μs-timescale atomistic molecular dynamics simulation in an explicit membrane environment. In response to a depolarizing membrane potential, the S4 helix undergoes an outward displacement, leading to changes in the VSD internal salt-bridge network, resulting in a reshaping of the permeation pathway and a significant increase in hydrogen bond connectivity throughout the channel. The total gating charge displacement associated with this transition is consistent with experimental estimates. Molecular docking calculations confirm the proposed mechanism for the inhibitory action of 2-guanidinobenzimidazole (2GBI) derived from electrophysiological measurements and mutagenesis. The depolarized structural model is also consistent with the formation of a metal bridge between residues located in the core of the VSD. Taken together, our results suggest that these structural models are representative of the closed and open states of the Hv1 channel.
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