Physical determinants of strong voltage sensitivity of K(+) channel block

Strong voltage sensitivity of inward-rectifier K(+) (Kir) channels has been hypothesized to arise primarily from an intracellular blocker displacing up to five K(+) ions from the wide, intracellular part of the ion conduction pore outwardly across the narrow ion selectivity filter. The validity of this hypothesis depends on two assumptions: i) that five ion sites are located intracellular to the filter, and ii) that the blocker can force essentially unidirectional K(+) movement in a pore region generally wider than the combined dimensions of the blocker plus a K(+) ion. Here, we present a crystal structure of the cytoplasmic portion of a Kir channel with five ions bound, and demonstrate that a constriction near the intracellular end of the pore, acting as a gasket, prevents K(+) ions from bypassing the blocker. This heretofore unrecognized “gasket” ensures that the blocker can effectively displace K(+) ions across the selectivity filter to generate exceedingly strong voltage sensitivity.