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  • Title: Structural basis of microtubule stabilization by laulimalide and peloruside A.
    Author: Prota AE, Bargsten K, Northcote PT, Marsh M, Altmann KH, Miller JH, Díaz JF, Steinmetz MO.
    Journal: Angew Chem Int Ed Engl; 2014 Feb 03; 53(6):1621-5. PubMed ID: 24470331.
    Abstract:
    Laulimalide and peloruside A 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 peloruside A bind to a unique non-taxane site on β-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/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.
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