Background:
Drugs that interfere with microtubule dynamics are used widely in cancer
chemotherapy. Microtubules are composed of αβ-tubulin heterodimers, and the colchicine binding
site of tubulin is an important pocket for designing tubulin polymerization inhibitors. We have
previously designed and synthesized a series of colchicine binding site inhibitors (CBSIs). However,
these compounds showed no anticancer activity in vivo. Then, we have used a deconstruction
approach to obtain a new derivative MT189, which showed in vivo anticancer activity.
Methods:
We crystallized a protein complex including two tubulins, one stathmin-like domain of
RB3 and one tubulin tyrosine ligase, and soaked MT189 into the crystals. We collected the
diffraction data and determined the tubulin-MT189 structure to 2.8 Å.
Results:
Here, we report the crystal structure of tubulin complexed with MT189, elucidate how the
small-molecular agent binds to tubulin and inhibits microtubule assembly, and explain previous
results of the structure-activity-relationship studies.
Conclusion:
The tubulin-MT189 complex structure reveals the interactions between this agent and
tubulin and provides insights into the design of new derivatives targeting the colchicine binding site.
Identification of potential tubulin polymerization inhibitors by 3D-QSAR, molecular docking and molecular dynamics
