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A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin

Author

Listed:
  • Grégory Menchon

    (Paul Scherrer Institut)

  • Andrea E. Prota

    (Paul Scherrer Institut)

  • Daniel Lucena-Agell

    (Consejo Superior de Investigaciones Cientificas CIB–CSIC)

  • Pascal Bucher

    (ETH Zürich)

  • Rolf Jansen

    (Helmholtz Zentrum für Infektionsforschung)

  • Herbert Irschik

    (Helmholtz Zentrum für Infektionsforschung)

  • Rolf Müller

    (Helmholtz Centre for Infection Research)

  • Ian Paterson

    (Cambridge University)

  • J. Fernando Díaz

    (Consejo Superior de Investigaciones Cientificas CIB–CSIC)

  • Karl-Heinz Altmann

    (ETH Zürich)

  • Michel O. Steinmetz

    (Paul Scherrer Institut
    University of Basel, Biozentrum)

Abstract

Microtubule-targeting agents (MTAs) like taxol and vinblastine are among the most successful chemotherapeutic drugs against cancer. Here, we describe a fluorescence anisotropy-based assay that specifically probes for ligands targeting the recently discovered maytansine site of tubulin. Using this assay, we have determined the dissociation constants of known maytansine site ligands, including the pharmacologically active degradation product of the clinical antibody-drug conjugate trastuzumab emtansine. In addition, we discovered that the two natural products spongistatin-1 and disorazole Z with established cellular potency bind to the maytansine site on β-tubulin. The high-resolution crystal structures of spongistatin-1 and disorazole Z in complex with tubulin allowed the definition of an additional sub-site adjacent to the pocket shared by all maytansine-site ligands, which could be exploitable as a distinct, separate target site for small molecules. Our study provides a basis for the discovery and development of next-generation MTAs for the treatment of cancer.

Suggested Citation

  • Grégory Menchon & Andrea E. Prota & Daniel Lucena-Agell & Pascal Bucher & Rolf Jansen & Herbert Irschik & Rolf Müller & Ian Paterson & J. Fernando Díaz & Karl-Heinz Altmann & Michel O. Steinmetz, 2018. "A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04535-8
    DOI: 10.1038/s41467-018-04535-8
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