Abstract
BackgroundA recent crystal structure of monastrol in a ternary complex with the kinesin Eg5 motor domain highlights a novel, induced-fit drug binding site at atomic resolution. Mutational obliteration of the monastrol binding site results in a monastrol-resistant, but otherwise catalytically active Eg5 motor domain. However, considering the conformational changes at this site, it is unclear what specific interactions stabilize the interaction between monastrol and the Eg5 motor domain.ResultsTo study the molecular complementarity of the monastrol-Eg5 interaction, we used a combination of synthetic chemistry and targeted mutations in Eg5 to measure the contribution of specific contacts to inhibition of Eg5 in vitro and in cultured cells. Structure-activity data on chemical derivatives, sequence analysis of Eg5 homologs from different species, and the effect of mutations near the drug binding site were consistent with the crystal structure.ConclusionThe mechanism of monastrol revealed by our data rationalizes its specificity for Eg5 over other kinesins and highlights a potential mechanism of drug resistance for anti-cancer therapy targeting this site in Eg5.
Highlights
A recent crystal structure of monastrol in a ternary complex with the kinesin Eg5 motor domain highlights a novel, induced-fit drug binding site at atomic resolution
The mechanism of monastrol revealed by our data rationalizes its specificity for Eg5 over other kinesins and highlights a potential mechanism of drug resistance for anti-cancer therapy targeting this site in Eg5
Guided by the atomic structure of the Eg5-ADP-monastrol ternary complex, we used a combination of synthetic chemistry, targeted mutagenesis, and protein biochemistry to characterize the interaction between the Eg5 motor domain and monastrol at the atomic level
Summary
A recent crystal structure of monastrol in a ternary complex with the kinesin Eg5 motor domain highlights a novel, induced-fit drug binding site at atomic resolution. Assessing the precise contributions of kinesins to highly dynamic processes during both interphase and mitosis is challenging. Genetic tools such as siRNA are general and specific, but lack temporal resolution and reversibility necessary for detailed analysis of dynamic processes. Inhibitors of Eg5 and other mitotic kinesins are plausible anti-cancer drugs under development and testing [11,12]. They (page number not for citation purposes)
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