Mechanisms of Action of Eg5 Inhibitors
Many inhibitors have now been described that bind specifically to Eg5. It is clear that inhibition is allosteric and that the binding of inhibitors influences motor activity largely by influencing the dynamics of nucleotide exchange, but surprisingly, whilst the residue requirements in the motor and the structure-activity relationships for the inhibitors have been examined by several groups, the allosteric molecular mechanisms by which inhibitors inhibit nucleotide exchange at the active site have not been widely discussed. The conformational cycle of the Eg5 motor is increasingly well understood, and understanding exactly how this cycle is arrested by inhibitors is an important problem. Here I briefly review current evidence on the structural mechanisms by which allosteric Eg5 inhibitors inhibit motor activity. I suggest that current Eg5 inhibitors work predominantly by stabilising the active site Mg2+ ion, and that they do this by stabilising the loop L5 in an apo-like conformation.
KeywordsSalt Bridge Inhibited State Motor Head Global Conformation Drug Binding Pocket
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