NSMB0607 RH.indd

Potassium channels show amazing discrimination, favoring K+ over other monovalent cations, such as Na+ and Li+. Although structural and functional studies have revealed much about the KcsA channel, including the residues physically involved in ion permeation and the conformational changes involved in channel opening, the basis for ion selectivity is still an open question. Now, MacKinnon and colleagues have used isothermal titration calorimetry (ITC) and new structural data to investigate how ions are selected by KcsA and the contributions they make in promoting the conductive state. ITC experiments using different monovalent and divalent cations, combined with the crystal structure of a KcsA mutant trapped in a nonconductive state, suggest that the heat measured upon K+ binding is correlated with the conformational change from the nonconductive to the conductive state. Furthermore, the authors implicate the ionic radius as an important determinant of K+ channel selectivity, as both monovalent and divalent cations similar in size or larger than K+, such as Cs+, Rb+ and Ba2+, bind within the channel, whereas those with radii similar to or smaller than Na+, including Li+ and Ca2+, do not. A crystal structure of KcsA with Ba2+ bound at the selectivity filter supports the correlation between sizeselective binding and adoption of the channel’s conductive state. Thus, the K+-dependent conformational change is a form of selectivity, occurring only when an ion of appropriate size binds. This is consistent with the ‘snug-fit’ hypothesis of Hille and Armstrong, proposed over 30 years ago. (PLoS Biol. 5, e121, 2007) MM