9RGN

SsCl at pH 6.5 + IVM - Partially opened

Summary for 9RGN

• Entry DOI: 10.2210/pdb9rgn/pdb
• EMDB information: 53951
• Descriptor: pH gated chloride channel, (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 -oxo-3',4',5',6,6',10,11,14,15,17,17a,20,20a,20b-tetradecahydro-2H,7H-spiro[11,15-methanofuro[4,3,2-pq][2,6]benzodioxacy clooctadecine-13,2'-pyran]-7-yl 2,6-dideoxy-4-O-(2,6-dideoxy-3-O-methyl-alpha-L-arabino-hexopyranosyl)-3-O-methyl-alpha-L-arabino-hexopyranoside (2 entities in total)
• Functional Keywords: ion channel, plgic, ph-sensitive channel, ivermectin, membrane protein
• Biological source: Sarcoptes scabiei
• Total number of polymer chains: 5
• Total formula weight: 203195.15

Authors

Kleiz-Ferreira, J.,Brams, M.,Harrison, P.J.,Gallagher, C.,Nys, M.,Donze, Y.,Quigley, A.,Bertrand, D.,Ulens, C. (deposition date: 2025-06-06, release date: 2026-03-18, Last modification date: 2026-04-22)

Primary citation

Kleiz-Ferreira, J.,Brams, M.,Harrison, P.J.,Gallagher, C.I.,Nys, M.,Donze, Y.,Quigley, A.,Bertrand, D.,Ulens, C.
Structure of a pH-sensitive pentameric ligand-gated ion channel from the Sarcoptes scabies mite.
Nat Commun, 17:-, 2026

PubMed 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.

PubMed: 41820392
DOI: 10.1038/s41467-026-70575-0

Experimental method

ELECTRON MICROSCOPY (3.1 Å)