Ion pathways in CLC transporters. (A) CLC-ec1 (Protein Data Bank accession no. 1OTS), showing one of the two identical subunits. Key features, including anion-binding sites (S_ex and S_cen) and mechanistically critical glutamate residues (E_ex and E_in), provide the framework for ion transport in CLCs in which pathways for Cl⁻ and H⁺ are shared through a portion of the protein and diverge at the center. (B) Four distinct rotameric configurations for E_ex. Cartoon depictions of the ion–pathway regions show E_ex in the previously known middle, down, and up configurations as well as in the new out position, which is accompanied by a configurational change of E_in.