Structural analysis of ion selectivity in the NaK channel

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Abstract
Ion selectivity is as important to ion channel function as channel gating. Much of what is currently known about selectivity comes from structural studies of K+-selective channels. Detailed structural analysis of the ion binding sites in the NaK pore provides a first look at the geometry and ionic selectivity in a Na+-permeable channel and may provide a basis for understanding permeation through nonselective cation channels. Here we present a detailed characterization of ion binding in the NaK pore using the high-resolution structures of NaK in complex with various cations. These structures reveal four ion binding sites with similar chemical environments but vastly different ion preference. The most nonselective of all is site 3, which is formed exclusively by backbone carbonyl oxygen atoms and resides deep within the selectivity filter. Additionally, four water molecules in combination with four backbone carbonyl oxygen atoms are seen to participate in K+ and Rb+ ion chelation, at both the external entrance and the vestibule of the NaK filter, confirming the channel's preference for an octahedral ligand configuration for K+ and Rb+ binding. In contrast, Na+ binding in the NaK filter, particularly at site 4, utilizes a pyramidal ligand configuration that requires the participation of a water molecule in the cavity. Therefore, the ability of the NaK filter to bind both Na+ and K+ ions seemingly arises from the ions' ability to use the existing environment in unique ways, rather than from any structural rearrangements of the filter itself.