A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin.
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Prota, Andrea E
Díaz, J Fernando
Steinmetz, Michel O
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AbstractMicrotubule-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.
AffiliationHelmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
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- Rhizoxin binding to tubulin at the maytansine-binding site.
- Authors: Takahashi M, Iwasaki S, Kobayashi H, Okuda S, Murai T, Sato Y
- Issue date: 1987 Dec 7
- [Inhibitors of tubulin assembly: specially on rhizoxin-maytansine site ligands].
- Authors: Iwasaki S
- Issue date: 1993 Aug
- A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs.
- Authors: Prota AE, Bargsten K, Diaz JF, Marsh M, Cuevas C, Liniger M, Neuhaus C, Andreu JM, Altmann KH, Steinmetz MO
- Issue date: 2014 Sep 23
- Maytansine and cellular metabolites of antibody-maytansinoid conjugates strongly suppress microtubule dynamics by binding to microtubules.
- Authors: Lopus M, Oroudjev E, Wilson L, Wilhelm S, Widdison W, Chari R, Jordan MA
- Issue date: 2010 Oct
- Maytansine inhibits nucleotide binding at the exchangeable site of tubulin.
- Authors: Huang AB, Lin CM, Hamel E
- Issue date: 1985 May 16