ArticleThe Journal of general physiology2021
A novel Hv1 inhibitor reveals a new mechanism of inhibition of a voltage-sensing domain.
Article in The Journal of general physiology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 13 citations in OpenAlex.
- Hv1 channel in immune cells and pharmacology.Pharmacological research · 2025Review
- 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
- 5-Chloro-2-Guanidinobenzimidazole (ClGBI) Is a Non-Selective Inhibitor of the Human HPharmaceuticals (Basel, Switzerland) · 2023Article
- The role of macrophage ion channels in the progression of atherosclerosis.Frontiers in immunology · 2023Review
- Effects of Mexiletine on a Race-specific Mutation in NaFrontiers in physiology · 2022Article
- RNA-Seq Analyses Reveal Roles of the HVCN1 Proton Channel in Cardiac pH Homeostasis.Frontiers in cell and developmental biology · 2022Article
- HIFs: New arginine mimic inhibitors of the Hv1 channel with improved VSD-ligand interactions.The Journal of general physiology · 2021Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Voltage-gated sodium, potassium, and calcium channels consist of four voltage-sensing domains (VSDs) that surround a central pore domain and transition from a down state to an up state in response to membrane depolarization. While many types of drugs bind pore domains, the number of organic molecules known to bind VSDs is limited. The Hv1 voltage-gated proton channel is made of two VSDs and does not contain a pore domain, providing a simplified model for studying how small ligands interact with VSDs. Here, we describe a ligand, named HIF, that interacts with the Hv1 VSD in the up and down states. We find that HIF rapidly inhibits proton conduction in the up state by blocking the open channel, as previously described for 2-guanidinobenzimidazole and its derivatives. HIF, however, interacts with a site slowly accessible in the down state. Functional studies and MD simulations suggest that this interaction traps the compound in a narrow pocket lined with charged residues within the VSD intracellular vestibule, which results in slow recovery from inhibition. Our findings point to a "wrench in gears" mechanism whereby side chains within the binding pocket trap the compound as the teeth of interlocking gears. We propose that the use of screening strategies designed to target binding sites with slow accessibility, similar to the one identified here, could lead to the discovery of new ligands capable of interacting with VSDs of other voltage-gated ion channels in the down state.
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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.