Scabies, caused by the tiny, contagious mite Sarcoptes scabiei, affects hundreds of millions of people worldwide and is becoming increasingly resistant to ivermectin (IVM), the frontline treatment. Although IVM is known to target parasite chloride channels, how IVM works in scabies mites has remained unclear. One likely target is SsCl, a pH-activated chloride channel from the pHCl family, a unique group of pentameric ligand-gated ion channels, whose gating mechanisms are still poorly understood. SsCl forms a cylindrical homopentamer, with five symmetrical subunits creating a central ion-conducting pore.

Using cryo-electron microscopy, electrophysiology and mutagenesis, Kleiz-Ferreira et al. resolved SsCl structures in four states — closed (pH 6.5), desensitized (pH 9), and both in complex with IVM — revealing a canonical pentameric pLGIC fold. Interestingly, the structure in a desensitized state adopts an unusual hourglass-shaped pore. IVM binds in the transmembrane region of SsCl at a conserved site between subunits, stabilized by key residues and interactions, and helps reshape the pore to promote ion flow.