5XAF

Crystal structure of tubulin-stathmin-TTL-Compound Z1 complex

5XAF の概要

• エントリーDOI: 10.2210/pdb5xaf/pdb
• 関連するPDBエントリー: 5XAG
• 分子名称: Tubulin alpha-1B chain, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, (3S,4R)-4-(3-hydroxy-4-methoxyphenyl)-3-methyl-1-(3,4,5-trimethoxyphenyl)azetidin-2-one, ... (14 entities in total)
• 機能のキーワード: tubulin, structural protein
• 由来する生物種: Bos taurus (Bovine); 詳細
• 細胞内の位置: Cytoplasm, cytoskeleton: P81947 Q6B856; Golgi apparatus : P63043
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 271017.74

構造登録者

Zhang, H.,Luo, C.,Wang, Y. (登録日: 2017-03-12, 公開日: 2017-12-20, 最終更新日: 2023-11-22)

主引用文献

Zhou, P.,Liang, Y.,Zhang, H.,Jiang, H.,Feng, K.,Xu, P.,Wang, J.,Wang, X.,Ding, K.,Luo, C.,Liu, M.,Wang, Y.
Design, synthesis, biological evaluation and cocrystal structures with tubulin of chiral beta-lactam bridged combretastatin A-4 analogues as potent antitumor agents
Eur J Med Chem, 144:817-842, 2017

PubMed Abstract: A diverse of chiral β-lactam bridged analogues of combretastatin A-4 (CA-4), 3-substituted 1,4-diaryl-2-azetidinones, were asymmetrically synthesized and biologically evaluated, leading to identify a number of potent anti-proliferative compounds represented by 14b and 14c with IC values of 0.001-0.021 μM, against four human cancer cell lines (A2780, Hela, SKOV-3 and MDA-MB-231). Structure-activity relationship (SAR) studies on all stereoisomers of 14b and 14c revealed that the absolute configurations of the chiral centers at 3- and 4-position were critically important for the activity and generally a trans configuration between the "A" and "B" rings is optimal. In addition, 14b and 14c displayed less cytotoxicity on normal human oviduct epithelial cells than malignant cells indicating good selectivity in vitro. Further biochemical evaluation and cocrystal structures with tubulin demonstrated that both compounds disrupted tubulin polymerization through interacting at the colchicine-binding site, suppressed angiogenesis in vitro and in vivo, blocked cell cycle progression at mitotic phase and induced cellular apoptosis. The in vivo assays verified that both compounds inhibited xenograft tumor growth in nude mice with acceptable therapeutic window, showing promising potentials for further clinical development.

PubMed: 29306206
DOI: 10.1016/j.ejmech.2017.12.004

実験手法

X-RAY DIFFRACTION (2.551 Å)