Figure 2: Molecular architecture of mammalian CLC molecules. (a) The composite structure of a generic CLC molecule consists of two parts: the membrane region, represented by the crystal structure of E. coli CLC molecule (CLC-ec1) (top), and the cytoplasmic domain represented by the crystal structure of the cytoplasmic domain of CLC-5. The two subunits are colored in green and blue, respectively. The two curve lines in the membrane portion roughly depict the transport pathways of ions (purple spheres). Red residues are Glu 148 of CLC-ec1, which correspond to Glu 232 of CLC-1. The negatively charged side chain of this residue obstructs the ion-transport pathway, and therefore is hypothesized to be the fast gate of CLC-channels. The two space-filled molecules in orange color in the cytoplasmic domains (one in each subunit) are ATP molecules seen in the crystal structure of the CLC-5’s cytoplasmic domain. Binding of ATP to CLC-1 inhibits the common gating of CLC-1. (b) X-ray crystal structure of CmCLC, a CLC protein from a thermophilic red alga Cyanidioschyzon merolae. Orange arrows point to the ATP-binding sites.