Proposed schematic model of NhaA transport. The transport mechanism occurs through a reorientation of the protein, alternately exposing a cavity containing Asp164 to the intracellular or the periplasmic space. The core domain is depicted as a blue square, and the panel domain is in beige. (1) The probable situation in the solved NhaA structure at low pH where the protein will be protonated. One of the protons (in orange) is likely to be bound to Asp164, and we hypothesize that the second proton (orange hashed) will interact with Lys300. Sodium ions (blue) will compete with protons for binding to Asp164, causing the Asp163–Lys300 salt bridge to break and possibly Lys300 to lose a proton (2). The sodium ion–bound protein will then switch to the outward-facing state (3). Upon release of the sodium ion, the protein will be reprotonated and the salt bridge between Lys300 and Asp163 reformed (4). The protein will then switch back to the inward-facing conformation.