Abstract
The high-resolution crystal structure of the voltage-gated sodium channel pore of NavMs from M. marinus (Bagneris et al, 2014) was previously solved in the presence and absence of channel blocker drugs. In this study, mutants were designed, expressed and characterised in order to block the transmembrane fenestrations that are proposed to enable ingress of drugs into the hydrophobilic binding cavity, and which subsequently block sodium ion translocation through the pore. Guided by the HOLE analysis programme (Smart et al, 1996) we identified critical residues in helix S6 adjacent to the fenestration. We were then able to produce a number of mutants with side chains of different sizes, aimed at narrowing or blocking the fenestration, in order to prevent drug entry into the internal pore cavity. Using circular dichroism (CD) spectroscopy we identified whether the mutants had any differential effect on channel stability in the presence/absence of the drugs, and then we used X-ray crystallography to determine the high resolution structures of the fenestration mutants. Supported by grants from the BBSRC.
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