The CLC proteins catalyze transport of chloride ions (Cl-) through cellular membranes in muscle, kidney, bone, and neurons. While some CLCs are ion channels others are H+-coupled secondary active transporters mediating the stoichiometric exchange of 2 Cl- for 1 H+. The exchange mechanism of the CLCs is unclear. Extensive structural and functional work suggests that the only conformational change taking place during transport is the movement of a conserved glutamate side chain in and out of the Cl- permeation pathway. However, other indirect lines of evidence suggest that regions distal to the Cl- pathway might also be involved in transport. To test whether transport entails only local or also global rearrangements we used the crystal structure of CLC-ec1, a prokaryotic CLC homologue, to introduce crosslinks at the contact points of helices J, O, P and Q. These helices do not line the Cl- or H+ pathways. We hypothesized that if exchange involves movement of these helices then these constraints should inhibit transport. In a cys-less background we introduced pairs of cysteines at different locations in this 4-helix bundle and used Hg2+ to crosslink them. All unreacted proteins mediated Cl-/H+ exchange at rates comparable to that of the WT. Reaction with Hg2+ results in a striking pattern: constraining residues facing the extracellular side has no effect, while targeting pairs towards the intracellular side induces progressively a more drastic reduction of activity. Finally, constraints placed close to the intracellular side results in inactive transporters. This reduction is not due to a Hg2+-induced distortion of the Cl- pathway, as the structure of the “locked-shut” protein is virtually identical to that of WT CLC-ec1. Removal of either gate removes the inhibitory effect of the crosslinks, suggesting that this conformational change is part of the allosteric coupling of the two gates rather than directly control the movement of a single gate. In conclusion, our results demonstrate that the CLC exchange cycle entails a conformational rearrangement of helices outside of the Cl- transport pathway that control the coupling between the two gates.