KcsA crystal structure as framework for a molecular model of the Na+ channel pore

The crystal structure of the pore-forming part of the KcsA bacterial K+-sel ective channel suggests a possible motif for related voltage-gated channels . We examined the hypothesis that the spacial orientation of the KcsA M1 an d M2 alpha-helices also predicts the backbone location of S5 and S6 helices of the voltage-gated Na+ channel. That channel's P region structure is exp ected to be different because selectivity is determined by side-chain inter actions rather than by main-chain carbonyls, and its outer vestibule accomm odates relatively large toxin molecules, tetrodotoxin (TTX) and saxitoxin ( STX), which interact with selectivity ring residues. The Na+ channel P loop was well-modeled by the alpha-helix-turn-beta-strand motif, which preserve s the relationships for toxin interaction with the Na+ channel found experi mentally. This outer vestibule was docked into the extracellular part of th e inverted teepee structure formed by the S5 and S6 helices that were spaci ally located by coordinates of the KcsA M1 and M2 helix main chains [Doyle et al. (1998) Science 280, 69-74], but populated with side chains of the re spective S5 and S6 structures, van der Waals contacts were optimized with m inimal adjustment of the S5, S6, and P loop structures, forming a densely p acked pore structure. Nonregular external S5-P and P-S6 segments were not m odeled here, except the P-S6 segment of domain II. The resulting selectivit y region structure is consistent with Nai channel permeation properties, of fering suggestions for the molecular processes involved in selectivity. The ability to construct a Na+ channel pore model consistent with most of the available biophysical and mutational information suggests that the KcsA str uctural framework may be conserved in voltage-gated channels.