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PDBsum entry 2ieh
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References listed in PDB file
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Key reference
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Title
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Structure of human eg5 in complex with a new monastrol-Based inhibitor bound in the r configuration.
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Authors
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I.Garcia-Saez,
S.Debonis,
R.Lopez,
F.Trucco,
B.Rousseau,
P.Thuéry,
F.Kozielski.
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Ref.
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J Biol Chem, 2007,
282,
9740-9747.
[DOI no: ]
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PubMed id
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Abstract
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Drugs that target mitotic spindle proteins have been proven useful for tackling
tumor growth. Eg5, a kinesin-5 family member, represents a potential target,
since its inhibition leads to prolonged mitotic arrest through the activation of
the mitotic checkpoint and apoptotic cell death. Monastrol, a specific
dihydropyrimidine inhibitor of Eg5, shows stereo-specificity, since
predominantly the (S)-, but not the (R)-, enantiomer has been shown to be the
biologically active compound in vitro and in cell-based assays. Here, we solved
the crystal structure (2.7A) of the complex between human Eg5 and a new keto
derivative of monastrol (named mon-97), a potent antimitotic inhibitor.
Surprisingly, we identified the (R)-enantiomer bound in the active site, and
not, as for monastrol, the (S)-enantiomer. The absolute configuration of this
more active (R)-enantiomer has been unambiguously determined via chemical
correlation and x-ray analysis. Unexpectedly, both the R- and the S-forms
inhibit Eg5 ATPase activity with IC(50) values of 110 and 520 nM (basal assays)
and 150 nm and 650 nm (microtubule-stimulated assays), respectively. However,
the difference was large enough for the protein to select the (R)- over the
(S)-enantiomer. Taken together, these results show that in this new monastrol
family, both (R)- and (S)-enantiomers can be active as Eg5 inhibitors. This
considerably broadens the alternatives for rational drug design.
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Figure 1.
FIGURE 1. Chemical structures of monastrol (A) and mon-97
(B).
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Figure 4.
FIGURE 4. Schematic view of the contacts between (R)-mon-97
(A) and (S)-monastrol (B) and residues of the Eg5
inhibitor-binding pocket using the program LIGPLOT (24).
Hydrophobic contacts (  3.9 Å) and hydrogen
bonds are depicted with red and green dashed lines,
respectively. The ethyl group of (S)-monastrol points toward the
solvent, whereas in the (R)-mon-97 structure the phenyl group
that substitutes the ethyl group is buried in the hydrophobic
pocket.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2007,
282,
9740-9747)
copyright 2007.
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