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Structure paper

TitleStructure of a pH-sensitive pentameric ligand-gated ion channel from the Sarcoptes scabies mite.
Journal, issue, pagesNat Commun, Year 2026
Publish dateMar 13, 2026
AuthorsJessica Kleiz-Ferreira / Marijke Brams / Peter J Harrison / Casey I Gallagher / Mieke Nys / Ysaline Donze / Andrew Quigley / Daniel Bertrand / Chris Ulens /
PubMed AbstractScabies 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- ...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.
External linksNat Commun / PubMed:41820392
MethodsEM (single particle)
Resolution3.1 - 4.24 Å
Structure data

53950

9rgm

EMDB-53950, PDB-9rgm:
SsCl at pH 6.5 - closed
Method: EM (single particle) / Resolution: 4.24 Å

53951

9rgn

EMDB-53951, PDB-9rgn:
SsCl at pH 6.5 + IVM - Partially opened
Method: EM (single particle) / Resolution: 3.1 Å

53952

9rgo

EMDB-53952, PDB-9rgo:
SsCl at pH 9 - Desensitized
Method: EM (single particle) / Resolution: 3.14 Å

53953

9rgp

EMDB-53953, PDB-9rgp:
SsCl at pH 9 + IVM - Opened
Method: EM (single particle) / Resolution: 3.65 Å

Chemicals

ChemComp-IVM:
(2aE,4E,5'S,6S,6'R,7S,8E,11R,13R,15S,17aR,20R,20aR,20bS)-6'-[(2S)-butan-2-yl]-20,20b-dihydroxy-5',6,8,19-tetramethyl-17

ChemComp-CL:
Unknown entry

Source
  • sarcoptes scabiei (arthropod)
KeywordsMEMBRANE PROTEIN / Ion channel / pLGIC / pH-sensitive channel / Ivermectin

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