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- W2019912010 abstract "Human Eg5, a mitotic motor of the kinesin superfamily, is involved in the formation and maintenance of the mitotic spindle. The recent discovery of small molecules that inhibit HsEg5 by binding to its catalytic motor domain leading to mitotic arrest has attracted more interest in Eg5 as a potential anticancer drug target. We have used hydrogen−deuterium exchange mass spectrometry and directed mutagenesis to identify the secondary structure elements that form the binding sites of new Eg5 inhibitors, in particular for S-trityl-l-cysteine, a potent inhibitor of Eg5 activity in vitro and in cell-based assays. The binding of this inhibitor modifies the deuterium incorporation rate of eight peptides that define two areas within the motor domain: Tyr125−Glu145 and Ile202−Leu227. Replacement of the Tyr125−Glu145 region with the equivalent region in the Neurospora crassa conventional kinesin heavy chain prevents the inhibition of the Eg5 ATPase activity by S-trityl-l-cysteine. We show here that S-trityl-l-cysteine and monastrol both bind to the same region on Eg5 by induced fit in a pocket formed by helix α3−strand β5 and loop L5−helix α2, and both inhibitors trigger similar local conformational changes within the interaction site. It is likely that S-trityl-l-cysteine and monastrol inhibit HsEg5 by a similar mechanism. The common inhibitor binding region appears to represent a “hot spot” for HsEg5 that could be exploited for further inhibitor screening." @default.
- W2019912010 created "2016-06-24" @default.
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- W2019912010 date "2004-09-25" @default.
- W2019912010 modified "2023-09-24" @default.
- W2019912010 title "Identification of the Protein Binding Region of <i>S</i>-Trityl-<scp>l</scp>-cysteine, a New Potent Inhibitor of the Mitotic Kinesin Eg5" @default.
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- W2019912010 doi "https://doi.org/10.1021/bi049264e" @default.
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