OPEN STATE STRUCTURE OF THE GATED MECHANOSENSOR MSCL

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The goal of the proposed research is to characterize an open (conducting) form of the mechanosensitve channel MscL. We will employ a several approaches including site-directed spin labeling, disulfide scanning and X-ray crystallography to elucidate the open state structure and mechanism of activation of this ion channel. Mechanosensitive channels have been found in all basic branches of the phylogenetic tree, and have been observerved in multiple tissue types in humans. A large percentage of current pharmaceuticals are targeted to ion channels, yet the mechanism of how these channels are opened and closed (gated) remains unknown. The recent structural determination of the mechanosensitive channel MscL in a closed conformation provided the first high resolution picture of this ubiquitous class of protein. The MscL protein is currently the only available system with which to study, at a high level of structural resolution, how ion channels are gated. To aid in crystallization, site-directed spin labeling and disulfide scanning studies will also be performed to both provide materail suitable for crystallization, i.e. in an open state, as well as determine more general information on channel gating.