1. Structural Biology and Molecular Biophysics
  2. Computational and Systems Biology
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The selectivity of the Na+/K+-pump is controlled by binding site protonation and self-correcting occlusion

  1. Huan Rui
  2. Pablo Artigas
  3. Benoît Roux  Is a corresponding author
  1. The University of Chicago, United States
  2. Texas Tech University Health Sciences Center, United States
Research Article
  • Cited 18
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Cite this article as: eLife 2016;5:e16616 doi: 10.7554/eLife.16616


The Na+/K+-pump maintains the physiological K+ and Na+ electrochemical gradients across the cell membrane. It operates via an 'alternating-access' mechanism, making iterative transitions between inward-facing (E1) and outward-facing (E2) conformations. Although the general features of the transport cycle are known, the detailed physicochemical factors governing the binding site selectivity remain mysterious. Free energy molecular dynamics simulations show that the ion binding sites switch their binding specificity in E1 and E2. This is accompanied by small structural arrangements and changes in protonation states of the coordinating residues. Additional computations on structural models of the intermediate states along the conformational transition pathway reveal that the free energy barrier toward the occlusion step is considerably increased when the wrong type of ion is loaded into the binding pocket, prohibiting the pump cycle from proceeding forward. This self-correcting mechanism strengthens the overall transport selectivity and protects the stoichiometry of the pump cycle.

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Author details

  1. Huan Rui

    Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6459-9871
  2. Pablo Artigas

    Department of Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center, Lubbock, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Benoît Roux

    Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, United States
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5254-2712


National Institutes of Health (U54-GM087519)

  • Benoît Roux

National Science Foundation (MCB-1515434)

  • Pablo Artigas

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Nir Ben-Tal, Tel Aviv University, Israel

Publication history

  1. Received: April 2, 2016
  2. Accepted: August 3, 2016
  3. Accepted Manuscript published: August 4, 2016 (version 1)
  4. Version of Record published: September 16, 2016 (version 2)


© 2016, Rui et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.


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