A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin.
Authors
Menchon, Grégory
Prota, Andrea E
Lucena-Agell, Daniel
Bucher, Pascal
Jansen, Rolf
Irschik, Herbert
Altmann, Karl-Heinz
Publication Date
2018-05-29Journal Title
Nature communications
ISSN
2041-1723
Publisher
Springer Nature
Volume
9
Issue
1
Pages
2106
Language
eng
Type
Article
This Version
VoR
Physical Medium
Electronic
Metadata
Show full item recordCitation
Menchon, G., Prota, A. E., Lucena-Agell, D., Bucher, P., Jansen, R., Irschik, H., Müller, R., et al. (2018). A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin.. Nature communications, 9 (1), 2106. https://doi.org/10.1038/s41467-018-04535-8
Abstract
Microtubule-targeting agents (MTAs) like taxol and vinblastine are amongst 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 -tubulin. The high resolution crystal structures of spongistatin-1 and disorazole Z in complex with tubulin allowed the definition of a novel 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.
Keywords
Microtubules, Animals, Humans, Macrolides, Maytansine, Oxazoles, Tubulin, Antineoplastic Agents, Ligands, Fluorescence Polarization, Binding Sites, Trastuzumab
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1038/s41467-018-04535-8
This record's URL: https://www.repository.cam.ac.uk/handle/1810/278957
Recommended or similar items
The following licence files are associated with this item: