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Science 10 August 2007:
Vol. 317. no. 5839, pp. 799 - 803
DOI: 10.1126/science.1142824

Reports

Mechanism of Na+/H+ Antiporting

Isaiah T. Arkin,1* Huafeng Xu,1 Morten Ø. Jensen,1 Eyal Arbely,2 Estelle R. Bennett,2 Kevin J. Bowers,1 Edmond Chow,1 Ron O. Dror,1 Michael P. Eastwood,1 Ravenna Flitman-Tene,2 Brent A. Gregersen,1 John L. Klepeis,1 István Kolossváry,1 Yibing Shan,1 David E. Shaw1,3{dagger}

Na+/H+ antiporters are central to cellular salt and pH homeostasis. The structure of Escherichia coli NhaA was recently determined, but its mechanisms of transport and pH regulation remain elusive. We performed molecular dynamics simulations of NhaA that, with existing experimental data, enabled us to propose an atomically detailed model of antiporter function. Three conserved aspartates are key to our proposed mechanism: Asp164 (D164) is the Na+-binding site, D163 controls the alternating accessibility of this binding site to the cytoplasm or periplasm, and D133 is crucial for pH regulation. Consistent with experimental stoichiometry, two protons are required to transport a single Na+ ion: D163 protonates to reveal the Na+-binding site to the periplasm, and subsequent protonation of D164 releases Na+. Additional mutagenesis experiments further validated the model.

1 D. E. Shaw Research, New York, NY 10036, USA.
2 The Hebrew University of Jerusalem, Department of Biological Chemistry, Jerusalem 91904, Israel.
3 Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA.

* On sabbatical leave from The Hebrew University of Jerusalem, Department of Biological Chemistry, Jerusalem, 91904, Israel.

{dagger} To whom correspondence should be addressed. E-mail: david{at}deshaw.com

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