ArticleProceedings of the National Academy of Sciences of the United States of America2016
On the role of water density fluctuations in the inhibition of a proton channel.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
What it found
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Who cites it
22 citing papers in PubMed, 38 citations in OpenAlex.
- HInternational journal of molecular sciences · 2025Review
- Fluctuating hydrogen-bond network of the Hv1 ion channel.Computational and structural biotechnology journal · 2025Article
- Interior pH-sensing residue of human voltage-gated proton channel HBiophysical journal · 2024Article
- Transcendent Aspects of Proton Channels.Annual review of physiology · 2024Review
- Review
- Trapping Charge Mechanism in Hv1 Channels (International journal of molecular sciences · 2023Article
- Role of voltage-gated proton channel (Hv1) in cancer biology.Frontiers in pharmacology · 2023Review
- Water Adsorption on Mica Surfaces with Hydrophilicity Tuned by Counterion Types (Na, K, and Cs) and Structural Fluorination.The journal of physical chemistry. C, Nanomaterials and interfaces · 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
- Analysis of an electrostatic mechanism for ΔpH dependent gating of the voltage-gated proton channel, HBiochimica et biophysica acta. Bioenergetics · 2021Review
- 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
- Engineered high-affinity zinc binding site reveals gating configurations of a human proton channel.The Journal of general physiology · 2020Article
- Water in Nanopores and Biological Channels: A Molecular Simulation Perspective.Chemical reviews · 2020Review
- Insights on small molecule binding to the Hv1 proton channel from free energy calculations with molecular dynamics simulations.Scientific reports · 2020Article
- Voltage-dependent structural models of the human Hv1 proton channel from long-timescale molecular dynamics simulations.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Scorpion toxin inhibits the voltage-gated proton channel using a ZnBritish journal of pharmacology · 2020Article
- Roles for Countercharge in the Voltage Sensor Domain of Ion Channels.Frontiers in pharmacology · 2020Review
- Hydrophobic gasket mutation produces gating pore currents in closed human voltage-gated proton channels.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
Hv1 is a transmembrane four-helix bundle that transports protons in a voltage-controlled manner. Its crucial role in many pathological conditions, including cancer and ischemic brain damage, makes Hv1 a promising drug target. Starting from the recently solved crystal structure of Hv1, we used structural modeling and molecular dynamics simulations to characterize the channel's most relevant conformations along the activation cycle. We then performed computational docking of known Hv1 inhibitors, 2-guanidinobenzimidazole (2GBI) and analogs. Although salt-bridge patterns and electrostatic potential profiles are well-defined and distinctive features of activated versus nonactivated states, the water distribution along the channel lumen is dynamic and reflects a conformational heterogeneity inherent to each state. In fact, pore waters assemble into intermittent hydrogen-bonded clusters that are replaced by the inhibitor moieties upon ligand binding. The entropic gain resulting from releasing these conformationally restrained waters to the bulk solvent is likely a major contributor to the binding free energy. Accordingly, we mapped the water density fluctuations inside the pore of the channel and identified the regions of maximum fluctuation within putative binding sites. Two sites appear as outstanding: One is the already known binding pocket of 2GBI, which is accessible to ligands from the intracellular side; the other is a site located at the exit of the proton permeation pathway. Our analysis of the waters confined in the hydrophobic cavities of Hv1 suggests a general strategy for drug discovery that can be applied to any ion channel.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.