5XAF

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

Summary for 5XAF

• Entry DOI: 10.2210/pdb5xaf/pdb
• Related: 5XAG
• Descriptor: 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)
• Functional Keywords: tubulin, structural protein
• Biological source: Bos taurus (Bovine); More
• Cellular location: Cytoplasm, cytoskeleton: P81947 Q6B856; Golgi apparatus : P63043
• Total number of polymer chains: 6
• Total formula weight: 271017.74

Authors

Zhang, H.,Luo, C.,Wang, Y. (deposition date: 2017-03-12, release date: 2017-12-20, Last modification date: 2023-11-22)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.551 Å)