Ca2+/cation antiporters catalyze the exchange of Ca2+ with various cations across biological membranes to regulate cytosolic calcium levels. The recently reported structure of a prokaryotic Na+/Ca 2+ exchanger (NCX-Mj) revealed its overall architecture in an outward-facing state. Here, we report the crystal structure of a H +/Ca2+ exchanger from Archaeoglobus fulgidus (CAX-Af) in the two representatives of the inward-facing conformation at 2.3 Å resolution. The structures suggested Ca2+ or H+ binds to the cation-binding site mutually exclusively. Structural comparison of CAX-Af with NCX-Mj revealed that the first and sixth transmembrane helices alternately create hydrophilic cavities on the intra- and extracellular sides. The structures and functional analyses provide insight into the mechanism of how the inward- to outward-facing state transition is triggered by the Ca2+ and H+ binding.
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