The Laulimalide tubulin binding site in microtubules unveiled
The Laulimalide tubulin binding site in microtubules unveiled.
Taxane-site MSAs like paclitaxel and epothilones are one of the most successful classes of chemotherapeutic drugs against cancer. However, their clinical application is hampered by toxicity and the development of resistance. The marine sponge products laulimalide and peloruside A (peloruside) are promising non-taxane-site MSAs (see Scheme 1). Both compounds potently inhibit the growth of multidrug-resistant cancer cells,and act synergistically with paclitaxel or epothilones in the promotion of microtubule stability and induction of cell death. These properties make laulimalide and peloruside potentially attractive next-generation MSAs for use in combination chemotherapy with taxane-site ligands. How this class of MSAs promote tubulin assembly and microtubule stability, and how they synergize with taxane-site drugs was not well understood.
CIB researchers of the group of Fernando Díaz have taken part in a study (Angew. Chem. Int. Ed. 2014, 53, 1 – 7) that, using X-ray crystallography has shown that laulimalide and peloruside A bind to a unique non-taxane site on b-tubulin and use their respective macrolide core structures to interact with a second tubulin dimer across protofilaments. Structures of ternary complexes of tubulin with laulimalide/peloruside A and epothilone A are also solved, and a crosstalk between the laulimalide/peloruside and taxane sites via the M-loop of β-tubulin is found. Together, the data define the mechanism of action of laulimalide and peloruside A on tubulin and microtubules. The data further provide a structural framework for understanding the synergy observed between two classes of MSAs in tubulin assembly and the inhibition of cancer cell growth.