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Structural Basis of Microtubule Stabilization by Discodermolide
Andrea E Prota1, Katja Bargsten1,2, Mariano Redondo-Horcajo3
1Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, OFLC/111, 5232, Villigen PSI, Switzerland.
Chembiochem : a European Journal of Chemical Biology
|February 17, 2017
Summary
Microtubule-stabilizing agents (+)-discodermolide (DDM) and KS-1-199-32 bind similarly to β-tubulin but stabilize its M-loop differently, revealing distinct binding mechanisms crucial for chemotherapy drug development.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- Microtubule-stabilizing agents (MSAs) are vital chemotherapy drugs.
- Understanding their binding mechanisms at a molecular level is key to developing more effective treatments.
Purpose of the Study:
- To elucidate the detailed binding modes of (+)-discodermolide (DDM) and a DDM-paclitaxel hybrid (KS-1-199-32) within the β-tubulin taxane pocket.
- To compare the structural effects and binding mechanisms of these two potent MSAs.
Main Methods:
- X-ray crystallography was employed to determine the high-resolution structures of DDM and KS-1-199-32 bound to β-tubulin.
- Structural analysis focused on the interactions within the taxane pocket and the stabilization of the M-loop.
Main Results:
- Both DDM and KS-1-199-32 adopt a similar hairpin conformation when binding to β-tubulin.
- KS-1-199-32 induces a distinct helical conformation in the M-loop, unlike DDM.
- Both compounds bridge β-tubulin helices H6/H7 and loop S9-S10 to the M-loop, similar to epothilone A but different from paclitaxel.
Conclusions:
- DDM and KS-1-199-32 exhibit differential binding mechanisms on β-tubulin, particularly in M-loop stabilization.
- These findings provide insights into the structure-activity relationships of MSAs and can inform the design of novel anticancer agents.
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