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PDBsum entry 2x7c
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References listed in PDB file
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Key reference
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Title
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Structural basis for inhibition of eg5 by dihydropyrimidines: stereoselectivity of antimitotic inhibitors enastron, Dimethylenastron and fluorastrol.
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Authors
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H.Y.Kaan,
V.Ulaganathan,
O.Rath,
H.Prokopcová,
D.Dallinger,
C.O.Kappe,
F.Kozielski.
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Ref.
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J Med Chem, 2010,
53,
5676-5683.
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PubMed id
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Abstract
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Human kinesin Eg5, which plays an essential role in mitosis by establishing the
bipolar spindle, has proven to be an interesting drug target for the development
of cancer chemotherapeutics. Here, we report the crystal structures of the Eg5
motor domain complexed with enastron, dimethylenastron, and fluorastrol. By
comparing these structures to that of monastrol and mon-97, we identified the
main reasons for increased potency of these new inhibitors, namely the better
fit of the ligand to the allosteric binding site and the addition of fluorine
atoms. We also noticed preferential binding of the S-enantiomer of enastron and
dimethylenastron to Eg5, while the R-enantiomer of fluorastrol binds
preferentially to Eg5. In addition, we performed a multidrug resistance (MDR)
study in cell lines overexpressing P-glycoprotein (Pgp). We showed that one of
these inhibitors may have the potential to overcome susceptibility to this
efflux pump and hence overcome common resistance associated with
tubulin-targeting drugs.
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