A three-dimensional electron density projection map of the ion-coupled membrane protein Escherichia coli Na+/H+ antiporter (NhaA) was recently published. Based on this projection map, and previous biophysical studies determining the assignment of the 12 transmembrane alpha-helices (TMHs), a three-dimensional molecular model of the NhaA was constructed, using interactive molecular graphics and energy calculations. The diuretic drug, amiloride, was docked into the model and putative interacting amino acids were identified. The model suggests that the pH dependent activity of NhaA may be explained by charge changes in the intracellular loop between TMH8 and TMH9 which alter the positions of TMHs 4, 5 and 11 relative to each other, such that a pore area of the transporter protein is opened.