Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 18, Issue 10, Pages 1159-U116Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2113
Keywords
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Funding
- US National Institutes of Health [GM062342]
- American Heart Association [BGIA2140172]
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The sodium-potassium (Na/K) pump is a P-type ATPase that generates Na+ and K+ concentration gradients across the cell membrane. For each hydrolyzed ATP molecule, the pump extrudes three Na+ and imports two K+ by alternating between outward-and inward-facing conformations that preferentially bind K+ or Na+, respectively. Remarkably, the selective K+ and Na+ binding sites share several residues, and how the pump is able to achieve the selectivity required for the functional cycle is unclear. Here, free energy-perturbation molecular dynamics (FEP/MD) simulations based on the crystal structures of the Na/K pump in a K+-loaded state (E2.P-i) reveal that protonation of the high-field acidic side chains involved in the binding sites is crucial to achieving the proper K+ selectivity. This prediction is tested with electrophysiological experiments showing that the selectivity of the E2P state for K+ over Na+ is affected by extracellular pH.
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