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.
Tubulin-tyrosine ligase catalyzes covalent binding of 3-fluoro-tyrosine to tubulin: kinetic and [19
F]NMR studies
