6FJF

Tubulin-FcMaytansine complex

6FJF の概要

• エントリーDOI: 10.2210/pdb6fjf/pdb
• 関連するPDBエントリー: 6FII
• 分子名称: Tubulin alpha-1B chain, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, DI(HYDROXYETHYL)ETHER, ... (14 entities in total)
• 機能のキーワード: cell cycle, tubulin fold, cytoskeleton, microtubule
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 266095.62

構造登録者

Menchon, G.,Prota, A.E.,Lucena Angell, D.,Bucher, P.,Mueller, R.,Paterson, I.,Diaz, J.F.,Altmann, K.-H.,Steinmetz, M.O. (登録日: 2018-01-22, 公開日: 2018-05-30, 最終更新日: 2025-04-23)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.402 Å)