2ieh
From Proteopedia
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'''Crystal structure of human kinesin Eg5 in complex with (R)-mon97, a new monastrol-based inhibitor that binds as (R)-enantiomer''' | '''Crystal structure of human kinesin Eg5 in complex with (R)-mon97, a new monastrol-based inhibitor that binds as (R)-enantiomer''' | ||
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| + | ==Overview== | ||
| + | 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. | ||
==About this Structure== | ==About this Structure== | ||
2IEH is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IEH OCA]. | 2IEH is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IEH OCA]. | ||
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| + | ==Reference== | ||
| + | Structure of human Eg5 in complex with a new monastrol-based inhibitor bound in the R configuration., Garcia-Saez I, DeBonis S, Lopez R, Trucco F, Rousseau B, Thuery P, Kozielski F, J Biol Chem. 2007 Mar 30;282(13):9740-7. Epub 2007 Jan 23. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17251189 17251189] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Plus-end-directed kinesin ATPase]] | [[Category: Plus-end-directed kinesin ATPase]] | ||
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[[Category: Beta-sheet core]] | [[Category: Beta-sheet core]] | ||
[[Category: Flanked by three alpha-helices on each side]] | [[Category: Flanked by three alpha-helices on each side]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | [[Category: Hydrolase]] |
| + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed May 14 11:38:22 2008'' | ||
Revision as of 08:38, 14 May 2008
Crystal structure of human kinesin Eg5 in complex with (R)-mon97, a new monastrol-based inhibitor that binds as (R)-enantiomer
Overview
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.
About this Structure
2IEH is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Structure of human Eg5 in complex with a new monastrol-based inhibitor bound in the R configuration., Garcia-Saez I, DeBonis S, Lopez R, Trucco F, Rousseau B, Thuery P, Kozielski F, J Biol Chem. 2007 Mar 30;282(13):9740-7. Epub 2007 Jan 23. PMID:17251189 Page seeded by OCA on Wed May 14 11:38:22 2008
