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.