A novel Hv1 inhibitor reveals a new mechanism of inhibition of a voltage-sensing domain

• DOI: 10.1085/jgp.202012833
• Publication Date: 2021-07-06T13:53:23Z
• Authors: Chang Zhao; Liang Hong; Saleh Riahi; Victoria T. Lim; Douglas J. Tobias; Francesco Tombola
• Keywords: 0301 basic medicine; Biomedical and Clinical Sciences; Physiology; Medical Physiology; Biological Sciences; 540; Article; Ion Channels; 03 medical and health sciences; 5.1 Pharmaceuticals; Medical physiology; Biochemistry and cell biology; Potassium; Biochemistry and Cell Biology; Protons; Zoology; Ion Channel Gating

Voltage-gated sodium, potassium, and calcium channels consist of four voltage-sensing domains (VSDs) that surround a central pore domain transition from down state to an up in response membrane depolarization. While many types drugs bind domains, the number organic molecules known VSDs is limited. The Hv1 voltage-gated proton channel made two does not contain domain, providing simplified model for studying how small ligands interact with VSDs. Here, we describe ligand, named HIF, interacts VSD states. We find HIF rapidly inhibits conduction by blocking open channel, as previously described 2-guanidinobenzimidazole its derivatives. however, site slowly accessible state. Functional studies MD simulations suggest this interaction traps compound narrow pocket lined charged residues within intracellular vestibule, which results slow recovery inhibition. Our findings point "wrench gears" mechanism whereby side chains binding trap teeth interlocking gears. propose use screening strategies designed target sites accessibility, similar one identified here, could lead discovery new capable interacting other ion