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A pathway of structural changes produced by monastrol binding to Eg5
Zoltan Maliga1, Jun Xing, Herbert Cheung
1Program in Biophysics, Harvard University, Boston, Massachusetts 02115, USA.
The Journal of Biological Chemistry
|January 26, 2006
Summary
Monastrol binding to Eg5 (a mitotic motor) causes structural changes, confirmed by spectroscopy in solution. This reveals the sequence of these drug-induced transitions, linking nucleotide binding to motor function.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Monastrol is a specific inhibitor of Eg5, a kinesin-5 mitotic motor essential for cell division.
- Crystallographic studies show monastrol induces structural changes in Eg5, but the dynamic sequence and solution relevance are unclear.
Purpose of the Study:
- To investigate the dynamic structural consequences of monastrol binding to Eg5 in solution.
- To determine the temporal sequence of drug-induced structural transitions using spectroscopic methods.
Main Methods:
- Utilized spectroscopic probes to monitor structural changes in Eg5 upon monastrol binding.
- Analyzed the kinetics of spectroscopic signal changes to establish the sequence of events.
Main Results:
- Spectroscopic data in solution confirmed the structural model of the Eg5-ADP-monastrol complex.
- The kinetics revealed the temporal order of drug-induced structural transitions.
- Identified loop L5 as a potential mediator linking nucleotide-binding site status to the neck linker.
Conclusions:
- Monastrol-induced structural changes observed in crystallography are relevant in solution at physiological concentrations.
- The study elucidates the dynamic mechanism of Eg5 inhibition by monastrol.
- Loop L5 plays a key role in allosteric regulation within kinesin motors.