This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.
Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.
2ieh
From Proteopedia
| Line 11: | Line 11: | ||
'''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''' | ||
| + | |||
| + | ==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]. | ||
| + | |||
| + | ==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]] | ||
| Line 21: | Line 27: | ||
[[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
