Figure 2.

Nearly magic-free mechanism for CLC Cl⁻/H⁺ transport. Cartoon depictions of the ion-binding regions show how the rotary movement of E_ex through its four configurations (middle, up, out, and down), coordinated with Cl⁻/H⁺ binding/unbinding/translocation, can achieve 2:1 Cl⁻/H⁺ antiport. For clarity, one direction of the transport cycle is depicted; however, the mechanism works in both directions. This mechanism avoids previous magic, in that (1) it does not require deprotonated E_ex to compete with Cl⁻ for the anion pathway, (2) the opening of the extracellular pathway in the out conformation provides a clear pathway for Cl⁻ ions, and (3) the rotation of E_in away from E113 allows H⁺ transport along water pathways and is thus consistent with the observation of coupled transport in CLC homologues that lack a titratable residue at the E_in position. The only remaining magical step concerns the inner gate, which is depicted here with dashed lines to indicate the uncertainty as to how and/or when the inner gate opens.