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

Human big conductance Caand 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 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 modelled 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.