Structural models of human big conductance calcium- and voltage-gated potassium channels

Abstract Human big conductance Ca 2+ - and voltage-gated K + channels (hBK) are putative drug targets for cardiovascular, respiratory and urological diseases. Here we have used molecular simulation and bioinformatics approaches to construct models of two domains important for Ca 2+ binding and channel gating, namely the regulator of conductance for K + (RCK1) domain and the so-called calcium bowl (CB). As templates for RCK1 were used the corresponding domains from a K + channel from E. coli and the K + channel from Methanobacterium thermoautothropicum (MthK). CB was modeled upon the structure of the human thrombospondin-1 C-terminal fragment and allowing the domain to relax in a simulated aqueous environment for 10-ns molecular dynamics simulations. The relevance of these models for interpreting the available molecular biology data is then discussed.