Structure of a pH-sensitive pentameric ligand-gated ion channel from the <i>Sarcoptes</i> scabies mite

Abstract Scabies is a skin infestation caused by the Sarcoptes scabiei mite. It produces a substantial global health burden, which is exacerbated by emerging resistance to prominent treatments, such as ivermectin. An anionic pentameric ligand-gated ion channel (pLGIC) identified in the mite, termed as SsCl, shows unique pH-sensitivity and is significantly modulated by ivermectin. Here, we use cryo-EM and electrophysiology to explore the pH-sensing mechanisms of SsCl and the impact of ivermectin on channel activity. Structures of SsCl were resolved under various pH conditions to capture a closed (pH 6.5) and desensitized (pH 9) state, alongside ivermectin-bound conformations. The desensitized structure adopts an unexpected “hourglass” conformation, suggesting the gating mechanisms may be more related to cation-selective channels. Structure-based analysis and mutagenesis highlighted extracellular histidine and glutamate residues which act as pH-sensors, revealing the protonation-dependent gating mechanism. Ivermectin binds at transmembrane subunit interfaces, stabilizing an open-pore conformation through hydrophobic interactions. Ivermectin bound-structures reveal a pH-dependent modulation, enhancing open-state prevalence at pH 9 and enabling atypical activation at pH 6.5, consistent with electrophysiological data. These structural and functional insights elucidate SsCl’s unique pH sensitivity and ivermectin’s mode of action, providing a foundation for designing next-generation therapeutics targeting this pathogen-related ion channel.