Structural Basis of Microtubule Stabilization by Laulimalide and Peloruside A

Laulimalide and pelorusideA are microtubule-stabilizing agents (MSAs), the mechanism of action on microtubules of which is poorly defined. Here, using X-ray crystallography it is shown that laulimalide and pelorusideA bind to a unique non-taxane site on -tubulin and use their respective macrolide core structures to interact with a second tubulin dimer across protofilaments. At the same time, they allosterically stabilize the taxane-site M-loop that establishes lateral tubulin contacts in microtubules. Structures of ternary complexes of tubulin with laulimalide/pelorusideA and epothiloneA are also solved, and a crosstalk between the laulimalide/peloruside and taxane sites via the M-loop of -tubulin is found. Together, the data define the mechanism of action of laulimalide and pelorusideA 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.