6FJM

tubulin-Disorazole Z complex

Summary for 6FJM

• Entry DOI: 10.2210/pdb6fjm/pdb
• Related: 6FII 6FJF
• Descriptor: Tubulin alpha-1B chain, Disorazole Z, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (12 entities in total)
• Functional Keywords: cell cycle, tubulin fold, cytoskeleton, microtubule
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 6
• Total formula weight: 265413.40

Authors

Menchon, G.,Prota, A.E.,Lucena Agell, D.,Bucher, P.,Jansen, R.,Irschik, H.,Mueller, R.,Paterson, I.,Diaz, J.F.,Altmann, K.-H.,Steinmetz, M.O. (deposition date: 2018-01-22, release date: 2018-05-30, Last modification date: 2024-01-17)

Primary citation

Menchon, G.,Prota, A.E.,Lucena-Agell, D.,Bucher, P.,Jansen, R.,Irschik, H.,Muller, R.,Paterson, I.,Diaz, J.F.,Altmann, K.H.,Steinmetz, M.O.
A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin.
Nat Commun, 9:2106-2106, 2018

PubMed 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.

PubMed: 29844393
DOI: 10.1038/s41467-018-04535-8

Experimental method

X-RAY DIFFRACTION (2.1 Å)