6FKJ

Tubulin-TUB075 complex

Summary for 6FKJ

• Entry DOI: 10.2210/pdb6fkj/pdb
• Descriptor: Tubulin alpha-1B chain, GUANOSINE-5'-DIPHOSPHATE, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (14 entities in total)
• Functional Keywords: cell cycle, tubulin fold, cytoskeleton, microtubule
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Cytoplasm, cytoskeleton: P81947 Q6B856; Golgi apparatus : P63043
• Total number of polymer chains: 6
• Total formula weight: 265663.70

Authors

Prota, A.E.,Steinmetz, M.O.,Priego, E.-M. (deposition date: 2018-01-24, release date: 2018-03-21, Last modification date: 2024-01-17)

Primary citation

Bueno, O.,Estevez Gallego, J.,Martins, S.,Prota, A.E.,Gago, F.,Gomez-SanJuan, A.,Camarasa, M.J.,Barasoain, I.,Steinmetz, M.O.,Diaz, J.F.,Perez-Perez, M.J.,Liekens, S.,Priego, E.M.
High-affinity ligands of the colchicine domain in tubulin based on a structure-guided design.
Sci Rep, 8:4242-4242, 2018

PubMed Abstract: Microtubule-targeting agents that bind at the colchicine-site of tubulin are of particular interest in antitumoral therapy due to their dual mechanism of action as antimitotics and vascular disrupting agents. Cyclohexanediones derivatives have been described as a new family of colchicine-domain binders with an association constant to tubulin similar to that of colchicine. Here, the high-resolution structures of tubulin in complex with cyclohexanediones TUB015 and TUB075 were solved by X-ray crystallography. A detailed analysis of the tubulin-TUB075 interaction by means of computational affinity maps allowed the identification of two additional regions at the binding site that were addressed with the design and synthesis of a new series of cyclohexanediones with a distal 2-substituted benzofurane. These new compounds showed potent antiproliferative activity with IC values in the nM range, arrested cell cycle progression at the G/M phase and induced apoptosis at sub μM concentrations. Moreover, they caused the destruction of a preformed vascular network in vitro and inhibited the migration of endothelial cells at non-toxic concentrations. Finally, these compounds displayed high affinity for tubulin as substantiated by a K value of 2.87 × 10 M which, to the best of our knowledge, represents the highest binding constant measured to date for a colchicine-domain ligand.

PubMed: 29523799
DOI: 10.1038/s41598-018-22382-x

Experimental method

X-RAY DIFFRACTION (2.148 Å)