Structural Insights into a Unique Inhibitor Binding Pocket in Kinesin Spindle Protein

Human kinesin Eg5 is a target for drug development in cancer chemotherapy with compounds in phase II clinical trials. These agents bind to a well-characterized allosteric pocket involving the loop L5 region, a structural element in kinesin-5 family members thought to provide inhibitor specificity. U...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2013-02, Vol.135 (6), p.2263-2272
Main Authors: Ulaganathan, Venkatasubramanian, Talapatra, Sandeep K, Rath, Oliver, Pannifer, Andrew, Hackney, David D, Kozielski, Frank
Format: Article
Language:English
Subjects:
Benzimidazoles - chemistry
Benzimidazoles - pharmacology
Binding Sites - drug effects
Crystallography, X-Ray
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
Kinesin - antagonists & inhibitors
Kinesin - chemistry
Kinesin - metabolism
Kinetics
Models, Molecular
Molecular Structure
Structure-Activity Relationship
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Summary:Human kinesin Eg5 is a target for drug development in cancer chemotherapy with compounds in phase II clinical trials. These agents bind to a well-characterized allosteric pocket involving the loop L5 region, a structural element in kinesin-5 family members thought to provide inhibitor specificity. Using X-ray crystallography, kinetic, and biophysical methods, we have identified and characterized a distinct allosteric pocket in Eg5 able to bind inhibitors with nanomolar K d. This pocket is formed by key structural elements thought to be pivotal for force generation in kinesins and may represent a novel site for therapeutic intervention in this increasingly well-validated drug target.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja310377d