Sodium/proton (Na + /H + ) antiporters, located at the plasma membrane in every cell, are vital for cell homeostasis 1 . In humans, their dysfunction has been linked to diseases, such as, hypertension, heart failure and epilepsy and they are well-established drug targets 2 . The best understood model system for Na + /H + antiport is NhaA from Escherichia coli 1,3 , where both EM and crystal structures are available [4][5][6] . NhaA is made up of two distinct domains, a Core domain and a Dimerisation domain. In the NhaA crystal structure a cavity is located between the two domains providing access to the ion-binding site from the inward-facing surface of the protein 1,4 . Like many Na + /H + antiporters, the activity of NhaA is regulated by pH, only becoming active above pH 6.5, where a conformational change is thought to occur 7 . To date, the only reported NhaA crystal structure is of the low pH inactivated form 4 . Here, we describe the active-state structure of a Na + / H + antiporter, NapA from Thermus thermophilus at 3 Å resolution, solved from crystals grown at pH 7.8. In the NapA structure, the Core and Dimerisation domains are in different positions to those seen in NhaA and a negatively charged cavity has now opened to the outside. The extracellular cavity allows access to a strictly conserved aspartate residue thought to directly coordinate ion-binding 1,8,9 , a role supported here by molecular dynamics simulations. To alternate access to this ion-binding site, however, requires a surprisingly large rotation of the Core domain, Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
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