A model for inactivation of KcsA channels as an allosteric process. Upon inactivation, there is a concerted transition of all four selectivity filter sequences (TVGYG) from the active conformation (green symbols) to the inactive conformation (red symbols). The conformation of the selectivity filter (the “active site” by analogy with allosteric enzymes) is regulated by networks of interactions between the pore helix and the external entrance of the channel that are formed independently within each subunit of the tetramer (the “regulatory sites” by analogy with allosteric enzymes). The selectivity filter sequence of each WT KcsA protomer is stabilized in its inactive conformation (striped symbols). On the other hand, the regulatory sites of E71A protomers are defective and do not support the stabilization of the inactive conformation of the selectivity filter sequences (open symbols). Under highly depolarizing potentials (top panel), the network of interactions is weakened (Cordero-Morales et al., 2006a). Under these conditions, the concerted transition of all four selectivity filter sequences into inactive conformations happens only when all four are stabilized by their regulatory site. When the membrane potential is negative (bottom panel), the network of interactions in the regulatory site becomes stronger. As a result, the concerted transition of the four selectivity filter sequences into inactive conformations occurs even when one of the sequences is not stabilized in the inactive conformation by its regulatory site. Pale red symbols correspond to unfavorable states of the KcsA channel.