jueves, 14 de agosto de 2014

A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs

A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs

A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs

  1. Michel O. Steinmetza,1
  1. Edited* by Susan Band Horwitz, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY, and approved July 15, 2014 (received for review May 3, 2014)


Microtubules are dynamic protein filaments assembled from tubulin subunits, which play a key role for cell division. Ligands that target microtubules and affect their dynamics belong to the most successful classes of chemotherapeutic drugs against cancer by inhibiting cell proliferation. Here we have analyzed three structurally unrelated drugs that destabilize microtubules, using X-ray crystallography. The data reveal a new tubulin-binding site for these drugs, which renders their mechanism of action distinct from that of other types of microtubule assembly inhibitors. Similar key interactions with tubulin are observed for all three ligands, thus defining a common pharmacophore. Our results offer an opportunity for the rational design of potent tubulin modulators for the development of more efficient cancer therapies.


The recent success of antibody–drug conjugates (ADCs) in the treatment of cancer has led to a revived interest in microtubule-destabilizing agents. Here, we determined the high-resolution crystal structure of the complex between tubulin and maytansine, which is part of an ADC that is approved by the US Food and Drug Administration (FDA) for the treatment of advanced breast cancer. We found that the drug binds to a site on β-tubulin that is distinct from the vinca domain and that blocks the formation of longitudinal tubulin interactions in microtubules. We also solved crystal structures of tubulin in complex with both a variant of rhizoxin and the phase 1 drug PM060184. Consistent with biochemical and mutagenesis data, we found that the two compounds bound to the same site as maytansine and that the structures revealed a common pharmacophore for the three ligands. Our results delineate a distinct molecular mechanism of action for the inhibition of microtubule assembly by clinically relevant agents. They further provide a structural basis for the rational design of potent microtubule-destabilizing agents, thus opening opportunities for the development of next-generation ADCs for the treatment of cancer.


  • Author contributions: A.E.P., K.B., J.F.D., J.M.A., K.-H.A., and M.O.S. designed research; A.E.P., K.B., M.M., M.L., and C.N. performed research; C.C. contributed new reagents/analytic tools; A.E.P., J.F.D., J.M.A., K.-H.A., and M.O.S. analyzed data; and A.E.P. and M.O.S. wrote the paper with support from all the authors.
  • The authors declare no conflict of interest.
  • *This Direct Submission article had a prearranged editor.
  • Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org [PDB ID code4TUY (T2R-TTL-rhizoxin F), 4TV9 (T2R-TTL-PM060184), 4TV8 (T2R-TTLmaytansine)].
  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1408124111/-/DCSupplemental.

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