Abstract

The lethal mutation C423D in Fusarium graminearum myosin I (FgMyoI) occurs close to the binding pocket of the allosteric inhibitor phenamacril and causes severe inhibition on mycelial growth of F. graminearum strain PH-1. Here, based on extensive Gaussian accelerated molecular dynamics simulations and wet experiments, we elucidate the underlying molecular mechanism of the abnormal functioning of the FgMyoIC423D mutant at the atomistic level. Our results suggest that the damaging mutation C423D exhibits a synergistic allosteric inhibition mechanism similar to but more robust than that of phenamacril, including effects on the active site and actin binding. Unlike phenamacril-induced closure of Switch2, the mutation results in unfolding of the N-terminal relay helix with a partially opened Switch2 and blocks the structural rearrangement of the relay/SH1 helices, impairing the proper initiation of the recovery stroke. Due to the significant influence of C423D mutation on the function of FgMyoI, designing covalent inhibitors targeting this site holds tremendous potential.

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