Novel compounds that specifically bind and modulate MscL: insights into channel gating mechanisms

What is it about?

Channels play a key role in an organism's ability to sense and respond to stimuli. Bacteria and other microbes often have channels that sense acute decreases in osmolarity and allow for the discharge of cellular solutes upon cell swelling, thus serving as biological "emergency release valves" that prevent cell lysis. One such channel is MscL, which opens a large pore, which is in fact the largest gated pore known in the biological world. Opening this pore inappropriately releases valuable solutes and is detrimental to the cell. This has led to the speculation that if one could find pharmacological agents that open MscL, they could be used as antibiotics. We have identified and studied two such pharmacological agents. Our data support the notion that MscL is a viable drug target, and agents that effect its opening may indeed be useful in treatment of microbial infections. We have also located the region within MscL that these agents bind and propose a potential mechanism of action for the agents. In addition, the binding site may be structurally analogous to features in other channels, and thus may give clues how to design pharmacological agents that affect other channels in other organisms, including mammals.

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