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dc.contributor.authorMaliga, Zoltan
dc.contributor.authorMitchison, Timothy J.
dc.date.accessioned2011-11-09T17:17:21Z
dc.date.issued2006
dc.identifier.citationMaliga, Zoltan, and Timothy J Mitchison. 2006. Small-molecule and mutational analysis of allosteric Eg5 inhibition by monastrol. BMC Chemical Biology 6: 2.en_US
dc.identifier.issn1472-6769en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:5343423
dc.description.abstractBackground: 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. 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. Results: To 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. Conclusion: 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.en_US
dc.language.isoen_USen_US
dc.publisherBioMed Centralen_US
dc.relation.isversionofdoi://10.1186/1472-6769-6-2en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC1448180/pdf/en_US
dash.licenseLAA
dc.titleSmall-Molecule and Mutational Analysis of Allosteric Eg5 Inhibition by Monastrolen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalBMC Chemical Biologyen_US
dash.depositing.authorMitchison, Timothy J.
dc.date.available2011-11-09T17:17:21Z
dash.affiliation.otherHMS^Systems Biologyen_US
dc.identifier.doi10.1186/1472-6769-6-2*
dash.contributor.affiliatedMitchison, Timothy


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