Na + /H + exchanger isoform one (NHE1) is a mammalian plasma membrane protein that removes intracellular protons, thereby elevating intracellular pH (pH i ). NHE1 uses the energy of allowing an extracellular sodium down its gradient into cells, to remove 1 intracellular proton. The ubiquitous protein has several important physiological and pathological influences on mammalian cells as a result of its activity. The three dimensional structure of human NHE1 (hNHE1) is not known. Here, we modeled

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... HE1 based on the structure of MjNhaP1 of Methanocaldoccocus jannaschii in combination with biochemical surface accessibility data. hNHE1 contained 12 transmembrane segments including a characteristic Na + /H + antiporter fold of two transmembrane (TM) segments with a helix-extended region-helix conformation, crossing each other within the membrane. Amino acids 363-410 mapped principally to the extracellular surface as an extracellular loop (EL5). A large preponderance of amino acids shown to be surface accessible by biochemical experiments, mapped near to, or on, the extracellular surface. Docking of Na + /H + exchanger inhibitors to the extracellular surface suggested that inhibitor binding on an extracellular site is made up from several amino acids of different regions of the protein. The results present a novel testable, three-dimensional model illustrating NHE1 structure and accounting for experimental biochemical data.