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Structural Basis of Microtubule Stabilization by Laulimalide and Peloruside A
Author(s) -
Prota Andrea E.,
Bargsten Katja,
Northcote Peter T.,
Marsh May,
Altmann KarlHeinz,
Miller John H.,
Díaz José Fernando,
Steinmetz Michel O.
Publication year - 2014
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201307749
Subject(s) - microtubule , tubulin , epothilone , taxane , chemistry , mechanism of action , stereochemistry , biophysics , biology , microbiology and biotechnology , biochemistry , cancer , genetics , in vitro , breast cancer
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.