Inward rectification is a fundamental but poorly understood phenomenon in potassium channel physiology. Despite its physiological importance, the exact mechanism has remained elusive. In this work, we uncover a previously unrecognized calcium-mediated gating mechanism in the MthK potassium channel that sheds new light on this essential process. By combining state-of-the-art proton-detected solid-state NMR spectroscopy with atomistic molecular dynamics simulations, we reveal that divalent calcium ions bind below the selectivity filter, physically obstructing the outward flow of potassium ions whereas inward flow is still possibleanalogous to a molecular ball check valve. Second, the binding of Ca 2+ to this site leads to stabilization of the selectivity filter and allows us to directly observe ion–ion interactions in the filter. These results offer direct experimental support for the long-debated “direct knock-on” mechanism, in which potassium ions move through the filter, without water cotransport.
Öster et al. (Sun,) studied this question.