Abstract
Scabies is a skin infestation caused by the mite Sarcoptes scabiei and represents a substantial global health burden exacerbated by emerging resistance to ivermectin. An anionic pentameric ligand-gated ion channel from the mite, SsCl, shows 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 in closed (pH 6.5) and desensitized (pH 9) states, alongside ivermectin-bound conformations. The desensitized structure adopts an unexpected hourglass conformation, suggesting a gating mechanism closer related to cation-selective channels. Structural analysis and mutagenesis identify extracellular histidine and glutamic acid residues that impact the pH-sensitivity, likely contributing to a broader pH-sensing network. Ivermectin-bound structures reveal pH-dependent modulation, enhancing open-state prevalence at pH 9 and enabling atypical activation at pH 6.5. These findings offer initial insights into SsCl’s pH-sensitivity and ivermectin’s activity, informing next-generation antiparasitic design.
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The atomic coordinates for the four structures, pH 6.5 closed, pH 9 desensitized, pH 6.5 with IVM, and pH 9 with IVM, have been deposited in the Protein Data Bank under accession codes PDB 9RGM, 9RGO, 9RGN, and 9RGP, respectively. The corresponding cryo-EM maps are deposited in the Electron Microscopy Data Bank under accession codes EMDB-53950, EMDB-53952, EMD-53951, and EMD-53953, respectively. The electrophysiological data generated in this study is provided as Source Data file. Source data are provided with this paper.
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Acknowledgements
This work was supported by an internal KU Leuven C1-grant C14/23/128 and a senior project grant from FWO-Vlaanderen G087921N to CU. JKF was supported by a post-doctoral mandate (PDM) from KU Leuven PDMt1/24/028. MN is a recipient of a FWO postdoctoral fellowship 12X2722N. CIG is a recipient of a FWO postdoctoral fellowship 1242724 N. The Membrane Protein Laboratory, including PJH and AQ, are funded by grant 223727/Z/21/Z from the Wellcome Trust, with additional support provided by Diamond Light Source and the Research Complex at Harwell, both Instruct-ERIC centres. We thank Diamond Light Source for access to the Cryo-EM facilities at the UK national electron bio-imaging centre (eBIC), proposal nt33941. We also thank Marcus Fislage and Dirk Reiter from VIB-VUB Facility for Bio Electron Cryogenic Microscopy (BECM), Brussels, Belgium, for the support with the data collection of SsCl at pH 6.5 (closed state). The data collection of SsCl at pH 9 (desensitized state) was supported by the iNEXT-Discovery project PID 30222. We thank Dr. Rebecca Howard for the data discussion.
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J.K.F. and C.U. conceived the project and acquired funding. J.K.F. performed virus production, protein expression, and FSEC; designed the mutants; prepared cryo-EM grids; processed cryo-EM data; built, refined, and validated the structural models; analyzed structural data; and conducted HOLE and phylogenetic analyses. M.B. prepared bacmid DNA, purified protein, and produced the mutants and mRNA. J.K.F. and P.J.H. collected cryo-EM data under the supervision of AQ; P.J.H. also provided intellectual input on cryo-EM data collection and image interpretation. Y.D. conducted electrophysiology experiments under the supervision of D.B. C.G. performed electrophysiology assays, microscopy of Sf9 cells, and analyzed electrophysiological data. M.N. contributed to the construct design and carried out detergent screening by FSEC. J.K.F. prepared all main structural figures and supplementary material. C.G. prepared electrophysiological data figures and the pLGIC sequence alignment. J.K.F. wrote the original manuscript. J.K.F., C.G., and C.U. were primarily responsible for reviewing and editing the manuscript with input from all authors. All authors reviewed and provided feedback on the final version. C.U. supervised the project.
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Kleiz-Ferreira, J., Brams, M., Harrison, P.J. et al. Structure of a pH-sensitive pentameric ligand-gated ion channel from the Sarcoptes scabies mite. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70575-0
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DOI: https://doi.org/10.1038/s41467-026-70575-0
